Method and composition for treating osteoporosis

ABSTRACT

This invention relates to a novel class of acidic amino acid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives of naturally occurring amino acids and their amides) useful as inhibitors of osteoclastogenesis. The invention also provides methods of using the novel class of acidic amino acid/dicarboxylic acid derivatives of the general formula ZOC—(CRR) m —COOH, wherein: m=2, 3 or 4; Z is OH or NH 2 ; one R in the compound is from the group consisting of SO 3 H, OSO 3 H, CH 2 —SO 3 H, CH 2 —OSO 3 H, and NHSO 3 H, and the remaining Rs are H or NH 2 , for inhibition of osteoclastogenesis.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/512,183, filed Oct. 20, 2003, whose contents are incorporated byreference.

FIELD OF THE INVENTION

This invention relates to a novel class of acidic aminoacid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives ofnaturally occurring amino acids and their amides) useful as inhibitorsof osteoclastogenesis. More particularly, this invention relates toinhibitors of osteoclastogenesis containing novel class of acidic aminoacid/dicarboxylic acid derivatives of the general formula:ZOC—(CRR)_(m)—COOH, wherein: m=2, 3 or 4; Z is OH or NH₂; one R in thecompound is from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H,CH₂—OSO₃H, and NHSO₃H, and the remaining Rs are H or NH₂. Thus, thecompounds may bear the general formula ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH,ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH or ZOC—CR₃R₄—CR₁R₂—COOH wherein Z is OH orNH₂, and R₁ to R₈ denotes H, NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H,NHSO₃H.

A pharmaceutical composition containing the aforementioned inhibitors ofosteoclastogenesis may also contain different divalent metal ions suchas Mg, Ca or Zn. The composition consists of varying amounts of theabove acidic amino acid/dicarboxylic acid derivatives and theirpharmaceutically acceptable selected alkali/alkaline earth metal salts.The invention also provides a process for the preparation of theaforesaid compounds, useful for the inhibition of the osteoclastdifferentiation, maturation and activation. These compounds can also beused for developing effective drugs for the treatment of osteoporosis,osteoarthritis, bone metastasis and bone loss in other metabolicdiseases of clinical importance.

-   1) The inhibitors of osteoclastogenesis also contain different    divalent metal ions such as Mg, Ca or Zn, wherein all the symbols    are the same meaning as hereinafter defined and non-toxic salts    thereof as an active ingredient,-   2) The composition consists of varying amounts of the above acidic    amino acid/dicarboxylic acid derivatives and their pharmaceutically    acceptable selected alkali/alkaline earth metal salts, wherein all    the symbols are the same meaning as hereinafter defined and    non-toxic salts thereof as an active ingredient,-   3) The process for the preparation of the aforesaid compounds,    useful for the inhibition of the osteoclast differentiation,    maturation and activation.-   4) These compounds can also be used for developing effective drugs    for the treatment of osteoporosis, osteoarthritis, bone metastasis    and bone loss in other metabolic diseases of clinical importance.

BACKGROUND OF THE INVENTION

Indian green mussels (Perna viridis) are the cheap source of proteinsand considered as a delicacy. Extract prepared from green mussels byenzyme-acid hydrolysis process showed various biological activities. Inour earlier patent (US patent application #20030044470) we have shownthe inhibition of osteoclast differentiation and activation in the crudeextract. In same continuation, attempts have been made to purify theactive compound that showed inhibition of osteoclast differentiation andactivation. The purification of the crude extract was done using HPLC,gel filtration and TLC methods. The purified compound was again checkedfor the above activity. The compound was characterized using NMR andLC-MS/MS techniques. This compound was synthesized and checked for thepresence of the above biological activity. This patent in particulardescribes the synthesis of the compound and also its activity forinhibition of osteoclast formation.

Novel class of amino acid/dicarboxylic acid derivatives (sulfonicacid/sulfate derivatives of naturally occurring amino acids and theiramides) along with calcium is for their activation to show inhibition ofthe osteoclastogenesis. Amino acid derivatives and calcium ion when usedseparately did not show any activity on inhibition of theosteoclastogenesis. The following classes of compounds are identified

-   (1) Natural acidic amino acids (Aspartic acid, Glutamic acid and    their amides),-   (2) Unnatural amino acids, amides such as homoglutamic acid,-   (3) Dicarboxylic acids such as succinic acid, glutaric acid, and    adipic acid-   (4) N-sulfonyl, C-sulfonyl/sulfate derivatives of the above acids-   (5) Alkaline earth metals such as Mg, Zn and Ca as their suitable    salts.    Related Arts

A lot of information is available on the matrix metalloproteinases(MMP's) commonly used as MMP inhibitors for the treatment ofosteoporosis (Nigel, R. A. Beeley, Phillip, R. J., Ansell, Andrew, J.P., Dochert, 1994, Curr. Opin. Ther. Patents., 4, 7-16). A cylindershaped solid compound has been prepared from the atelocollagen solution,L-alanine solution and bone morphogenetic protein for treating bone lossand elevating bone deformities (Hiroo, Akhihiko, Rebecca, Wozney,Seeherman, 2003, WO Patent #2003066083). In another study glutamate andglutamate derivatives/analogs or their mixtures have been used formodulating the bone quality (Tadeusz, Jose Luis; Stefan, 2003, WO Patent# 2003043626). Toshhiro (2003) invented a compound consisting ofinteracting trans-activators with glutamic acid, aspartic acid and richcarboxyl-terminal domain for estrogen receptor dependent activity(Toshihiro, 2002, WO Patent # 2003000730). Glutamic acid has beendefined as an effective neuromediator and one of its derivatives isinvolved in osteoclast formation and bone resorption. The modificationof glutamic acid action in bone could be used for bone remodeling(Hopital E. Herriot, Lyon Fr., 2002, Microscopy Research and technique,58(2), 70-76).

However, these inhibitors have various problems and efforts were madefor the development of non-peptide inhibitors. For instance in thespecification of EP 606046, several aryl-sulfonamide derivatives havebeen described. In another invention several aryl sulfonyl amino acidderivatives of the following specifications have been described (Sakaki,Kanazawa, Sugiura, Miyazaki, Ohno, 2002, U.S. Pat. No. 6,403,644) as MMPinhibitors:

-   1) N-[[4-(Benzoylamino)phenyl]sulfonyl]glycine,-   2) N-[[3-(Benzoylamino)phenyl]sulfonyl]glycine,-   3) N-[[2-(Benzoylamino)phenyl]sulfonyl]glycine,-   4) N-[[4-(Acetylamino)phenyl]sulfonyl]glycine,-   5) N-[[4-(Phenylacetylamino)phenyl]sulfonyl]glycine,-   6) N-[[4-[(Phenylethylcarbonyl)amino]phenyl]sulfonyl]glycine,-   7) N-[[4-(Cinnamoylamino)phenyl]sulfonyl]glycine,-   8) N-[[4-(N-Phenylureido)phenyl]sulfonyl]glycine,-   9) N-[[4-(N-Phenylthioureido)phenyl]sulfonyl]glycine,-   10) N-[[4-[(Benzyloxycarbonyl)amino]phenyl]sulfonyl]glycine,-   11) N-[[4-[(Phenyloxymethylcarbonyl)amino]phenyl]sulfonyl]glycine,-   12) N-[[4-[(Benzyloxymethylcarbonyl)amino]phenyl]sulfonyl]glycine,-   13) N-[[4-(4-Methoxybenzoylamino)phenyl]sulfonyl]glycine,-   14) N-[[4-(4-Fluorobenzoylamino)phenyl]sulfonyl]glycine,-   15) N-[[4-(4-Nitrobenzoylamino)phenyl]sulfonyl]glycine,-   16) N-[[4-(3-Nitrobenzoylamino)phenyl]sulfonyl]glycine,-   17) N-[[4-(2-Nitrobenzoylamino)phenyl]sulfonyl]glycine,-   18) N -[[4-(4-Formylbenzoylamino)phenyl]sulfonyl]glycine,-   19) N-[[4-(Benzoylamino)phenyl]sulfonyl]-D-alpha-phenylglycine,-   20) N-[[4-(Benzoylamino)phenyl]sulfonyl]-L-alpha-phenylglycine,-   21)    N-[[4-(4-Methylbenzoylamino)phenyl]sulfonyl]-D-alpha-phenylglycine,-   22)    N-[[4-(Methylbenzoylamino)phenyl]sulfonyl]-L-alpha-phenylglycine,-   23)    N-[[4-(4-Methoxybenzoylamino)phenyl]sulfonyl]-D-alpha-phenylglycine,-   24)    N-[[4-(4-Methoxybenzoylamino)phenyl]sulfonyl]-L-alpha-phenylglycine,-   25)    N-[[4-(4-Fluorobenzoylamino)phenyl]sulfonyl]-D-alpha-phenylglycine,-   26)    N-[[4-(4-Fluorobenzoylamino)phenyl]sulfonyl]-L-alpha-phenylglycine,-   27)    N-[[4-(4-Nitrobenzoylamino)phenyl]sulfonyl]-D-alpha-phenylglycine,-   28)    N-[[4-(4-Nitrobenzoylamino)phenyl]sulfonyl]-L-alpha-phenylglycine,-   29) N -[(4-Pivaloyloxyphenyl)sulfonyl]-D,L-alpha-phenylglycine,-   30) N-[(4-Pivaloyloxyphenyl)sulfonyl]-D,L-phenylalanine,-   31) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]glycine,-   32) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D,L-alanine,-   33) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-beta-alanine,-   34) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-valine,-   35) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D,L-valine,-   36) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-Ieucine,-   37) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D,L-Ieucine,-   38) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D,L-serine,-   39)    N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-phenylalanine,-   40) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-tyrosine,-   41) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D,L-alanine    methyl ester,-   42) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-valine methyl    ester,-   43) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D,L-valine    methyl ester,-   44) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-Ieucine    methyl ester,-   45) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-D,L-serine    methyl ester,-   46) N-[[4-(2,4-Dichlorobenzoylamino)phenyl]sulfonyl]-L-tyrosine    methyl ester,-   47) N-[[4-(3-Nitrobenzoylamino)phenyl]sulfonyl]-L-aspartic acid,-   48) N-[[3-(3-Nitrobenzoylamino)phenyl]sulfonyl]-L-aspartic acid,-   49) N-[[4-(3-Aminobenzoylamino)phenyl]sulfonyl]-L-aspartic acid,-   50) N-[[3-(3-Aminobenzoylamino)phenyl]sulfonyl]-L-aspartic acid,-   51) N-[[4-(Benzoylamino)phenyl]sulfonyl]-L-glutamic acid,-   52) N-[[4-(4-Chlorobenzoylamino)phenyl]sulfonyl]-L-glutamic acid,-   53) N-[[4-(4-Nitrobenzoylamino)phenyl]sulfonyl]-L-glutamic acid,-   54)    N-[[4-[2-(4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-D,L-3-morpholinoalanine    ethyl ester,-   55)    N-[[4-[2-(4-(1-Nitrophenyl)butyryloxy]phenyl]sulfonyl]-D,L-3-morpholinoalanine    ethyl ester,-   56)    N-[[4-(2-Methoxy-2-phenylacetyloxy)phenyl]sulfonyl]-D,L-3-morpholinoalanine    ethyl ester,-   57)    N-[[4-[[[1-(4-Nitrophenyl)cyclobutyl]carbonyl]oxy]phenyl]sulfonyl]-D,L-3-morpholinoalanine    ethyl ester,-   58)    N-[[3-Methyl-4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-t-butoxycar-L-lysine,-   59) N-[[4-(2-Phenylbutyryloxy)phenyl]sulfonyl]glycine,-   60)    N-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-D,L-phenylalanine,-   61)    N-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-D,L-aspartic    acid,-   62)    N-[[4-[[[1-(4-Nitrophenyl)cyclobutyl]carbonyl]oxy]phenyl]sulfonyl]-D,L-aspartic    acid,-   63)1-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonylamide]-1-cyclopropanecarboxylic    acid,-   64)    N-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-D,L-2-(2-furanyl)glycine,-   65)    N-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-D,L-2-(2-tri-enyl)glycine,-   66)    N-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-L-valine,-   67)    N-[[4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-S-carboxymethyl-L-cysteine,-   68)    N-[[4-[2-Ethyl-2-(4-methoxyphenyl)butyryloxy]phenyl]sulfonyl]-glycine,-   69)    N-[[3-Methyl-4-[2-[4-(1-Pyrrolidinyl)phenyl]butyryloxy]phenyl]sulfonyl]-L-lysine,-   70) N-[[3    Methyl-4-[2-[4-(1-pyrrolidinyl)phenyl]butylyloxy]phenyl]sulfonyl]amino]pentanoic    acid,-   71) N-[[(3-Methyl-4-pivaloyloxy)phenyl]sulfonyl]-beta-alanine.    Purpose of the Invention

Bone is a metabolically active and highly organized connective tissue.The main functions of the bones are provision of mechanical andstructural support, maintaining blood calcium levels, supportinghaematopoiesis and housing the important vital organs such as brain,spinal cord and heart. To accomplish these functions bone needscontinuous remodeling. Bone contains two distinct cell types, theosteoblasts, essential for bone formation (synthesis); and theosteoclasts, essential for bone resorption (break down). Morphogenesisand remodeling of bone involves the synthesis of bone matrix byosteoblasts and coordinated resorption by osteoclasts. The co-ordinationbetween the osteoblasts and osteoclasts is very crucial in maintainingbone homeostasis and structural integrity of the skeleton. Both theseprocesses are influenced by several hormones and local factors generatedwithin bone and bone marrow, resulting in a complex network of controlmechanisms. An imbalance of osteoblast and osteoclast functions canresult in skeletal abnormalities characterized by increased or decreasedbone mass. This may leads to excessive bone loss that reflects thebalance of bone formation and bone resorption. Bone destruction orresorption is carried out by haematopoietically derived osteoclasts.Their number and activity is determined by cell lineage allocation,proliferation and differentiation of osteoclast precursors and theresorptive efficiency of mature osteoclasts. Important bone diseasessuch as osteoporosis, rheumatoid arthritis, Paget's disease of bone andbone metastasis of breast and prostate cancers are caused by increasedosteoclast activity (Teitelbaum, 2000). In these disorders boneresorption exceeds bone formation resulting in decreased skeletal mass.This causes bones to become thin, fragile and susceptible to fracture.The consequences of osteoporotic bone fractures include chronic pain inbone, body deformity including height loss and muscle weakness.Therefore, to understand both pathogenesis and successful treatment ofthese bone diseases there is a need for better understanding of biologyof osteoclasts.

Osteoporosis is now a serious problem that imposes substantiallimitations on the affected individuals. In human, 1 in 3 women and 1 in12 men over 45 years are at risk of suffering painful and deformingfractures as a result of osteoporosis. More women die after hipfractures than from cancers of ovaries, cervix and uterus. Osteoporosisoccurs at a relatively earlier age in Indian males and females comparedto western countries (Gupta, 1996). A variety of disadvantages areassociated with current therapeutic agents used in osteoporosis andother metabolic bone disorders. The side effects of current therapiesinclude increase in the risk of breast and uterine cancers, uppergastrointestinal distress and induction of immune responses. Drugs thatinhibit the formation or activity of osteoclasts and with no toxicityand harmful side effects will be valuable for treating osteoporosis andother bone diseases. Bone resorption and loss of calcium from bone arecomplications associated with arthritis, many cancers and with bonemetastases of breast and prostate tumors. Because of lack of researchinto osteoporosis and related diseases, we don't know all the answers totreat these diseases. Progress in better understanding the pathogenesisand successful treatment of these diseases to date has targetedosteoclast. Osteoclasts, the only cells capable of resorbing bonedifferentiate from the haemopoietic precursors of monocyte/macrophagelineage that also give rise to macrophages and dendritic cells (Miyamotoet al. 2001). Lineage choice and the differentiation process is guidedby lineage restricted key regulatory molecules and transcriptionfactors. Osteoclasts are large multinucleated cells. They are formed bythe fusion of mononuclear cells of haemopoietic origin and not bymitosis, since DNA synthesis is not required. Osteoclast formation andbone resorption is regulated by many hormones, growth factors and immunecell-derived cytokines (Udagawa et al. 1995, Wani et al. 1999, Fox etal. 2000, Fuller et al. 2000). These factors act directly or indirectlyvia other cell types to influence osteoclast differentiation. The mostimportant cell type influencing osteoclast formation is osteoblast,which promote this process by a contact-dependent mechanism. Recentadvances revealed that two molecules, macrophage colony stimulatingfactor (M-CSF) and receptor activator of NF-κB ligand (RANKL) expressedby osteoblasts are essential and sufficient for the differentiation ofhaemopoietic cells to form osteoclasts (Tanaka et al. 1993, Anderson etal., 1997, Wong et al. 1997, Lacey et al. 1998, Yasuda et al. 1998). Theprecise role of other cells, such as T lymphocytes in bone homeostasisis yet to be fully elucidated. It has recently been reported thatactivated T cells regulates osteoclast formation by some unknownmechanisms. T cells support osteoclast formation by RANKL-dependent andRANKL-independent mechanisms (Weitzmann et al. 2001). Cytokines producedby activated T cells, as well as by other cell types regulatesosteoclastogenesis in physiological and pathological conditions. Recentdiscovery of RANKL has enabled us for the meticulous dissection ofmechanisms by which various factors regulate osteoclastogenesis, andbetter understanding of both pathogenesis and successful treatment bonediseases. In our preliminary studies, we have investigated the role ofnovel compounds on osteoclastogenesis induced by RANKL in the presenceof M-CSF in stromal cell-free cultures of osteoclast precursors.

Natural products from plants and organisms have frequently been used asa source for development of effective drugs. There is an increasedinterest in analysis of natural products from marine organisms. Seaanimals contain metabolites which can be used for treatment of manydiseases.

The inventors have previously shown (US Patent #2003066083) that a novelextract (mussel hydrolysate) prepared from the Indian green mussel(Perna viridis) inhibits the osteoclast differentiation in murinehaemopoietic precursors of monocyte/macrophage cell lineage. The extractalso inhibits the bone resorbing activity of osteoclasts. There wasapproximately 80-90% inhibition of osteoclast formation and boneresorption in the presence of extract. More importantly, the extract isnon-toxic to other cells and is useful to prepare a drug for thetreatment of osteoporosis and other bone diseases.

In further investigation, at each stages of purification we found asignificant inhibition of osteoclast formation and bone resorption(60-90%). We have purified some active components from extract and theseactive components significantly inhibit both osteoclast formation andbone resorption. These active compounds can be used in therapeuticsettings to protect and cure the individuals against osteoporosis andother metabolic bone diseases.

The current known therapeutic agents have a variety of associateddisadvantages. The side effects of current therapies include an elevatedrisk of breast and uterine cancers, upper gastrointestinal distress andinduction of immune responses (Watts' 1999). Our earlier US Patent(#2003066083) describes preparation of mussell hydrolysate from theIndian green mussel (Perna viridis) and its inhibition of the osteoclastdifferentiation in murine hemopoietic precursors of monocyte/macrophagecell lineage. The extract also shows inhibition of the bone resorbingactivity of osteoclasts.

The present inventors have found that a series of novel sulfonicacid/sulfate derivatives of acidic amino acids, aspartic acids, glutamicacid, homoglutamic acid and their related aliphatic dicarboxylic acids(Succinic acid, glutaric acid and adipic acid) have inhibitory activityagainst osteoclast formation and bone resorption. These compounds arenovel and non-toxic to other cells. The active compounds may play avital role in inhibition of differentiation of osteoclast fromhemopoietic precursors and can be used in therapeutic settings toprotect and cure the individuals against osteoporosis and othermetabolic bone diseases.

SUMMARY OF THE INVENTION

This invention relates to a novel class of acidic aminoacid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives ofnaturally occurring amino acids and their amides) useful as inhibitorsof osteoclastogenesis. The invention also provides methods of using thenovel class of acidic amino acid/dicarboxylic acid derivatives of thegeneral formula ZOC—(CRR)_(m)—COOH, wherein: m=2, 3 or 4; Z is OH orNH₂; one R in the composition is from the group consisting of SO₃H,OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining Rs are H orNH₂. Thus, the compounds may bear the general formulaZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH, ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH orZOC—CR₃R₄—CR₁R₂—COOH wherein Z is OH or NH₂, and R₁ to R₈ denotes H,NH₂, SO₃H, or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H. Mixtures of thesecompounds may be administered, as well.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is related to:

A) Osteoclast inhibitors containing novel class of acidic aminoacid/dicarboxylic acid derivatives (sulfonic acid/sulfate derivatives ofnaturally occurring amino acids and their amides);

B) Osteoclast inhibitors containing novel class of acidic aminoacid/dicarboxylic acid derivatives of the general formulaZOC—(CRR)_(m)—COOH, wherein: m=2, 3 or 4; Z is OH or NH₂; one R in thecomposition is from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H,CH₂—OSO₃H, and NHSO₃H, and the remaining Rs are H or NH₂. Thus,compounds may bear the general formula:ZOC—CR₃R₄—CR₁R₂—COOH  (Ia)ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH  (Ib)ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH  (Ic)wherein:

-   -   Z is OH or NH₂; and    -   R₁ to R₈ are H, NH₂, SO₃H or OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, NHSO₃H.        And this includes the following class of compounds:

-   1. A compound in which Z═OH, R₁═NHSO₃H, R₂═R₃═R₄═H is the same    meaning as hereinbefore defined;

-   2. A compound in which Z═OH, R₁═NH₂, R₃═R₄═H, R₂═SO₃H is the same    meaning as hereinbefore defined;

-   3. A compound in which Z═OH, R₁═NH₂, R₃═R₄═H, R₂═OSO₃H is the same    meaning as hereinbefore defined;

-   4. A compound in which Z═OH, R₁═NH₂, R₂═R₄═H, R₃═SO₃H is the same    meaning as hereinbefore defined;

-   5. A compound in which Z═OH, R₁═NH₂, R₂═R₄═H, R₃═OSO₃H is the same    meaning as hereinbefore defined;

-   6. A compound in which Z═OH, R₁═NH₂, R₂═R₃═H, R₄═SO₃H is the same    meaning as hereinbefore defined;

-   7. A compound in which Z═OH, R₁═NH₂, R₂═R₃═H, R₄═OSO₃H is the same    meaning as hereinbefore defined;

-   8. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═CH₂SO₃H is the same    meaning as hereinbefore defined;

-   9. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═CH₂OSO₃H is the same    meaning as hereinbefore defined;

-   10. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═SO₃H is the same    meaning as hereinbefore defined;

-   11. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═OSO₃H is the same    meaning as hereinbefore defined;

-   12. A compound in which Z═OH, R₂═NHSO₃H, R₁═R₃═R₄═H is the same    meaning as hereinbefore defined;

-   13. A compound in which Z═OH, R₂═H, R₁═CH₂SO₃H is the same meaning    as hereinbefore defined;

-   14. A compound in which Z═OH, R₂═H, R₁═CH₂OSO₃H is the same meaning    as hereinbefore defined;

-   15. A compound in which Z═OH, R₂═H, R₁═SO₃H is the same meaning as    hereinbefore defined;

-   16. A compound in which Z═OH, R₂═H, R₁═OSO₃H is the same meaning as    hereinbefore defined;

-   17. A compound in which Z═OH, R₂═NH₂, R₃═R₄═H, R₁═SO₃H is the same    meaning as hereinbefore defined;

-   18. A compound in which Z═OH, R₂═NH₂, R₃═R₄═H, R₁═SO₃H is the same    meaning as hereinbefore defined;

-   19. A compound in which Z═OH, R₂═NH₂, R₁═R₄═H, R₃═SO₃H is the same    meaning as hereinbefore defined;

-   20. A compound in which Z═OH, R₂═NH₂, R═R₄═H, R₃═OSO₃H is the same    meaning as hereinbefore defined;

-   21. A compound in which Z═OH, R₂═NH₂, R₁═R₃═H, R₄═SO₃H is the same    meaning as hereinbefore defined;

-   22. A compound in which Z═OH, R₂═NH₂, R₁═R₃═H, R₄═OSO₃H is the same    meaning as hereinbefore defined;

-   23. A compound in which R₁═NHSO₃H, R₂═R₃═R₄═H is the same meaning as    hereinbefore defined;

-   24. A compound in which Z═NH₂, R₁═H, R₂═CH₂SO₃H is the same meaning    as hereinbefore defined;

-   25. A compound in which Z═NH₂, R₁═H, R₂═CH₂OSO₃H is the same meaning    as hereinbefore defined;

-   26. A compound in which Z═NH₂, R₁═H, R₂═SO₃H is the same meaning as    hereinbefore defined;

-   27. A compound in which Z═NH₂, R₁═H, R₂═OSO₃H is the same meaning as    hereinbefore defined;

-   28. A compound in which Z═R₁═NH₂, R₂═R₄═H, R₂═SO₃H is the same    meaning as hereinbefore defined;

-   29. A compound in which Z═R₁═NH₂, R₂═R₄═H, R₃═OSO₃H is the same    meaning as hereinbefore defined;

-   30. A compound in which Z═R₁═NH₂, R₂═R₄═H, R₃═SO₃H is the same    meaning as hereinbefore defined;

-   31. A compound in which Z═R₁═NH₂, R₂═R₄═H, R₃═OSO₃H is the same    meaning as hereinbefore defined;

-   32. A compound in which Z═R₁═NH₂, R₂═R₃═H, R₄═SO₃H is the same    meaning as hereinbefore defined;

-   33. A compound in which Z═R₁═NH₂, R₂═R₃═H, R₄═OSO₃H is the same    meaning as hereinbefore defined;

-   34. A compound in which Z═NH₂, R₂═NHSO₃H, R₁═R₃═R₄═H is the same    meaning as hereinbefore defined;

-   35. A compound in which Z═NH₂, R₂ to R₄═H, R₁═CH₂SO₃H is the same    meaning as hereinbefore defined;

-   36. A compound in which Z═NH₂, R₂ to R₄═H, R₁═CH₂SO₃H is the same    meaning as hereinbefore defined;

-   37. A compound in which Z═OH, R₂ to R₄═H, R₁═SO₃H is the same    meaning as hereinbefore defined;

-   38. A compound in which Z═OH, R₂ to R₄═H, R₁═OSO₃H is the same    meaning as hereinbefore defined;

-   39. A compound in which Z═R₂═NH₂, R₃═R₄═H, R₁═SO₃H is the same    meaning as hereinbefore defined;

-   40. A compound in which Z═R₂═NH₂, R₃═R₄═H, R₁═OSO₃H is the same    meaning as hereinbefore defined;

-   41. A compound in which Z═R₂═NH₂, R₁═R₄═H, R₃═SO₃H is the same    meaning as hereinbefore defined;

-   42. A compound in which Z═R₂═NH₂, R₁═R₄═H, R₃═OSO₃H is the same    meaning as hereinbefore defined;

-   43. A compound in which Z═R₂═NH₂, R₁═R₃═H, R₄═SO₃H is the same    meaning as hereinbefore defined;

-   44. A compound in which Z═R₂═NH₂, R₁═R₃═H, R₄═OSO₃H is the same    meaning as hereinbefore defined;

-   45. A compound in which Z═OH, R₁═NHSO₃H, R₂═R₃═R₄═R₅═R₆═H is the    same meaning as hereinbefore defined;

-   46. A compound in which Z═OH, R₁, R₃ to R₆═H, R₂═CH₂SO₃H is the same    meaning as hereinbefore defined;

-   47. A compound in which Z═OH, R₁, R₃ to R₆═H, R₂═CH₂OSO₃H is the    same meaning as hereinbefore defined;

-   48. A compound in which Z═OH, R₁, R₃ to R₆═H, R₂═SO₃H is the same    meaning as hereinbefore defined;

-   49. A compound in which Z═OH, R₁, R₃ to R₆═H, R₂═OSO₃H is the same    meaning as hereinbefore defined;

-   50. A compound in which Z═OH, R₂ to R₆═H, R₁═OSO₃H is the same    meaning as hereinbefore defined;

-   51. A compound in which Z═OH, R₂ to R₆═H, R₁═SO₃H is the same    meaning as hereinbefore defined;

-   52. A compound in which Z═OH, R₁═NH₂, R₃ to R₆═H, R₂═SO₃H is the    same meaning as hereinbefore defined;

-   53. A compound in which Z═OH, R₁═NH₂, R₃ to &═H, R₂═OSO₃H is the    same meaning as hereinbefore defined;

-   54. A compound in which Z═OH, R₁═NH₂, R₂═H, R₄ to R₆═H, R₃═SO₃H is    the same meaning as hereinbefore defined;

-   55. A compound in which Z═OH, R₁═NH₂, R₂═H, R₄ to R₆═H, R₃═OSO₃H is    the same meaning as hereinbefore defined;

-   56. A compound in which Z═OH, R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═SO₃H is the    same meaning as hereinbefore defined;

-   57. A compound in which Z═OH, R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═OSO₃H is the    same meaning as hereinbefore defined;

-   58. A compound in which Z═OH, R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═SO₃H is the    same meaning as hereinbefore defined;

-   59. A compound in which Z═OH, R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═OSO₃H is the    same meaning as hereinbefore defined;

-   60. A compound in which Z═OH, R₁═NH₂, R₂ to R₅═H, R₆═SO₃H is the    same meaning as hereinbefore defined;

-   61. A compound in which Z═OH, R₁═NH₂, R₂ to R₅═H, R₆═OSO₃H is the    same meaning as hereinbefore defined;

-   62. A compound in which Z═OH, R₂═NHSO₃H, R₁, R₃ to R₆═H is the same    meaning as hereinbefore defined;

-   63. A compound in which Z═OH, R₂ to R₆═H, R₁═CH₂SO₃H is the same    meaning as hereinbefore defined;

-   64. A compound in which Z═OH, R₂ to R₆═H, R₁═CH₂OSO₃H is the same    meaning as hereinbefore defined;

-   65. A compound in which Z═OH, R₂═NH₂, R₃ to R₆H, R₁═SO₃H is the same    meaning as hereinbefore defined;

-   66. A compound in which Z═OH, R₂═NH₂, R₃ to R₆H, R₁═OSO₃H is the    same meaning as hereinbefore defined;

-   67. A compound in which Z═OH, R₂═NH₂, R₁, R₄ to R₆H, R₃═SO₃H is the    same meaning as hereinbefore defined;

-   68. A compound in which Z═OH, R₂═NH₂, R₁, R₄ to R₆H, R₃═OSO₃H is the    same meaning as hereinbefore defined;

-   69. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═SO₃H is the    same meaning as hereinbefore defined;

-   70. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═OSO₃H is the    same meaning as hereinbefore defined;

-   71. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═SO₃H is the    same meaning as hereinbefore defined;

-   72. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═OSO₃H is the    same meaning as hereinbefore defined;

-   73. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═SO₃H is the    same meaning as hereinbefore defined;

-   74. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═OSO₃H is the    same meaning as hereinbefore defined;

-   75. A compound in which Z═NH₂, R₁═NHSO₃H, R₂ to R₆═H is the same    meaning as hereinbefore defined;

-   76. A compound in which Z═R₁═NH₂, R₃ to R₆═H, R₂═SO₃H is the same    meaning as hereinbefore defined;

-   77. A compound in which Z═R₁═NH₂, R₃ to R₆═H, R₂═OSO₃H is the same    meaning as hereinbefore defined;

-   78. A compound in which Z═R₁═NH₂, R₂═H, R₃ to R₆═H, R₃═SO₃H is the    same meaning as hereinbefore defined;

-   79. A compound in which Z═R₁═NH₂, R₂═H, R₃ to R₆═H, R₃═OSO₃H is the    same meaning as hereinbefore defined;

-   80. A compound in which Z═R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═SO₃H is the same    meaning as hereinbefore defined;

-   81. A compound in which Z═R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═OSO₃H is the    same meaning as hereinbefore defined;

-   82. A compound in which Z═R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═SO₃H is the same    meaning as hereinbefore defined;

-   83. A compound in which Z═R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═OSO₃H is the    same meaning as hereinbefore defined;

-   84. A compound in which Z═R₁═NH₂, R₂ to R₅═H, R₆═SO₃H is the same    meaning as hereinbefore defined;

-   85. A compound in which Z═R₁═NH₂, R₂ to R₅═H, R₆═OSO₃H is the same    meaning as hereinbefore defined;

-   86. A compound in which Z═NH₂, R₁, R₃ to R₆═H, R₂═CH₂SO₃H is the    same meaning as hereinbefore defined;

-   87. A compound in which Z═NH₂, R₁, R₃ to R₆═H, R₂═CH₂OSO₃H is the    same meaning as hereinbefore defined;

-   88. A compound in which Z═NH₂, R₁, R₃ to R₆═H, R₂═SO₃H is the same    meaning as hereinbefore defined;

-   89. A compound in which Z═NH₂, R₁, R₃ to R₆═H, R₂═OSO₃H is the same    meaning as hereinbefore defined;

-   90. A compound in which Z═NH₂, R₂ to R₆═H, R₁═OSO₃H is the same    meaning as hereinbefore defined;

-   91. A compound in which Z═NH₂, R₂ to R₆═H, R₁═SO₃H is the same    meaning as hereinbefore defined;

-   92. A compound in which Z═NH₂, R₂═NHSO₃H; R₁═H, R₃ to R₆═H is the    same meaning as hereinbefore defined;

-   93. A compound in which Z═NH₂, R₂ to R₆═H, R₁═CH₂SO₃H is the same    meaning as hereinbefore defined;

-   94. A compound in which Z═NH₂, R₂ to R₆═H, R₁═CH₂OSO₃H is the same    meaning as hereinbefore defined;

-   95. A compound in which Z═NH₂, R₂═NH₂, R₃ to R₆═H, R₁═SO₃H is the    same meaning as hereinbefore defined;

-   96. A compound in which Z═NH₂, R₂═NH₂, R₃ to R₆═H, R₁═OSO₃H is the    same meaning as hereinbefore defined;

-   97. A compound in which Z═NH₂, R₂═NH₂, R₁, R₄ to R₆H, R₃═SO₃H is the    same meaning as hereinbefore defined;

-   98. A compound in which Z═R₂═NH₂, R₁, R₄ to & H, R₃═OSO₃H is the    same meaning as hereinbefore defined;

-   99. A compound in which Z═R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═SO₃H is the same    meaning as hereinbefore defined;

-   100. A compound in which Z═R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═OSO₃H is the    same meaning as hereinbefore defined;

-   101. A compound in which Z═R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═SO₃H is the    same meaning as hereinbefore defined;

-   102. A compound in which Z═R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═OSO₃H is the    same meaning as hereinbefore defined;

-   103. A compound in which Z═R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═SO₃H is the    same meaning as hereinbefore defined;

-   104. A compound in which Z═R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═OSO₃H is the    same meaning as hereinbefore defined;

-   105. A compound in which Z═OH, R₁═NHSO₃H, R₂ to R₈═H is the same    meaning as hereinbefore defined;

-   106. A compound in which Z═OH, R₁, R₃ to R₈═H, R₂═CH₂SO₃H is the    same meaning as hereinbefore defined;

-   107. A compound in which Z═OH, R₁, R₃ to R₈═H, R₂═CH₂OSO₃H is the    same meaning as hereinbefore defined;

-   108. A compound in which Z═OH, R₁, R₃ to R₈═H, R₂═SO₃H is the same    meaning as hereinbefore defined;

-   109. A compound in which Z═OH, R₁, R₃ to R₈═H, R₂═OSO₃H is the same    meaning as hereinbefore defined;

-   110. A compound in which Z═OH, R₁═NH₂, R₃ to R₈═H, R₂═SO₃H is the    same meaning as hereinbefore defined;

-   111. A compound in which Z═OH, R₁═NH₂, R₃ to R₈═H, R₂═OSO₃H is the    same meaning as hereinbefore defined;

-   112. A compound in which Z═OH, R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═SO₃H is    the same meaning as hereinbefore defined;

-   113. A compound in which Z═OH, R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═OSO₃H is    the same meaning as hereinbefore defined;

-   114. A compound in which Z═OH, R₁═NH₂, R₂═R₃═H, R₅ to R₈═H, R₄═SO₃H    is the same meaning as hereinbefore defined;

-   115. A compound in which Z═OH, R₁═NH₂, R₂═R₃═H, R₅ to R₈═H, R₄═OSO₃H    is the same meaning as hereinbefore defined;

-   116. A compound in which Z═OH, R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H,    R₅═SO₃H is the same meaning as hereinbefore defined;

-   117. A compound in which Z═OH, R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H,    R₅═OSO₃H is the same meaning as hereinbefore defined;

-   118. A compound in which Z═OH, R₁ ═N—H₂, R₂═R₅═H, R₇═R₈═H, R₆═SO₃H    is the same meaning as hereinbefore defined;

-   119. A compound in which Z═OH, R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═OSO₃H is    the same meaning as hereinbefore defined;

-   120. A compound in which Z═OH, R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═SO₃H is    the same meaning as is before defined;

-   121. A compound in which Z═OH, R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═OSO₃H is    the same meaning as hereinbefore defined;

-   122. A compound in which Z═OH, R₁═NH₂, R₂ to R₇═H, R₈═SO₃H is the    same meaning as hereinbefore defined;

-   123. A compound in which Z═OH, R₁═NH₂, R₂ to R₇═H, R₈═OSO₃H is the    same meaning as hereinbefore defined;

-   124. A compound in which Z═OH, R₂═NHSO₃H, R₁, R₃ to R₈═H is the same    meaning as hereinbefore defined;

-   125. A compound in which Z═OH, R₂ to R₈═H, R₁═CH₂SO₃H is the same    meaning as hereinbefore defined;

-   126. A compound in which Z═OH, R₂ to R₈═H, R₁═CH₂OSO₃H is the same    meaning as hereinbefore defined;

-   127. A compound in which Z═OH, R₂ to R₈═H, R₁═SO₃H is the same    meaning as hereinbefore defined;

-   128. A compound in which Z═OH, R₂ to R₈═H, R₁═OSO₃H is the same    meaning as hereinbefore defined;

-   129. A compound in which Z═OH, R₂═NH₂, R₃ to R₈═H, R₁═SO₃H is the    same meaning as hereinbefore defined;

-   130. A compound in which Z═OH, R₂═NH₂, R₃ to R₈═H, R₁═OSO₃H is the    same meaning as hereinbefore defined;

-   131. A compound in which Z═OH, R₂═NH₂, R₁, R₄ to R₈═H, R₃═SO₃H is    the same meaning as hereinbefore defined;

-   132. A compound in which Z═OH, R₂═NH₂, R₁, R₄ to R₈═H, R₃═OSO₃H is    the same meaning as hereinbefore defined;

-   133. A compound in which Z═OH, R₂═NH₂, R₁═R₃═H, R₅ to R₈═H, R₄═SO₃H    is the same meaning as hereinbefore defined;

-   134. A compound in which Z═OH, R₂═NH₂, R₁═R₃═H, R₅ to R₈═H, R₄═OSO₃H    is the same meaning as hereinbefore defined;

-   135. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H,    R₅═SO₃H is the same meaning as is before defined;

-   136. A compound in which Z═OH, R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H,    R₅═OSO₃H is the same meaning as hereinbefore defined;

-   137. A compound in which Z═OH, R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,    R₆═SO₃H is the same meaning as hereinbefore defined;

-   138. A compound in which Z═OH, R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,    R₆═OSO₃H is the same meaning as hereinbefore defined;

-   139. A compound in which Z═OH, R₂═NH₂, R₁═R₈═H, R₃ to R₆═H, R₇═SO₃H    is the same meaning as hereinbefore defined;

-   140. A compound in which Z═OH, R₂═NH₂, R₁═R₈═H, R₃ to R₆═H, R₇═OSO₃H    is the same meaning as hereinbefore defined;

-   141. A compound in which Z═OH, R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═SO₃H is    the same meaning as hereinbefore defined;

-   142. A compound in which Z═OH, R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═OSO₃H is    the same meaning as hereinbefore defined;

-   143. A compound in which Z═NH₂, R₁═NHSO₃H, R₂ to R₈═H is the same    meaning as hereinbefore defined;

-   144. A compound in which Z═NH₂, R₁ and R₃ to R₈═H, R₂═CH₂SO₃H is the    same meaning as hereinbefore defined;

-   145. A compound in which Z═NH₂, R₁ and R₃ to R₈═H, R₂═CH₂OSO₃H is    the same meaning as hereinbefore defined;

-   146. A compound in which Z═NH₂, R₁ and R₃ to R₈═H, R₂═SO₃H is the    same meaning as hereinbefore defined;

-   147. A compound in which Z═NH₂, R₁ and R₃ to R₈═H, R₂═OSO₃H is the    same meaning as hereinbefore defined;

-   148. A compound in which Z═R₁═NH₂, R₃ to R₈═H, R₂═SO₃H is the same    meaning as hereinbefore defined;

-   149. A compound in which Z═R₁═NH₂, R₃ to R₈═H, R₂═OSO₃H is the same    meaning as hereinbefore defined;

-   150. A compound in which Z═R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═SO₃H is the    same meaning as hereinbefore defined;

-   151. A compound in which Z═R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═OSO₃H is the    same meaning as hereinbefore defined;

-   152. A compound in which Z═R₁═NH₂, R₂═R₃═H, R₅ to R₈═H, R₄═SO₃H is    the same meaning as hereinbefore defined;

-   153. A compound in which Z═R₁═NH₂, R₂═R₃═H, R₅ to R₈═H, R₄═OSO₃H is    the same meaning as hereinbefore defined;

-   154. A compound in which Z═R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H, R₅═SO₃H    is the same meaning as hereinbefore defined;

-   155. A compound in which Z═R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H, R₅═OSO₃H    is the same meaning as hereinbefore defined;

-   156. A compound in which Z═R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═SO₃H is the    same meaning as hereinbefore defined;

-   157. A compound in which Z═R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═OSO₃H is the    same meaning as hereinbefore defined;

-   158. A compound in which Z═R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═SO₃H is the    same meaning as hereinbefore defined;

-   159. A compound in which Z═R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═OSO₃H is the    same meaning as hereinbefore defined;

-   160. A compound in which Z═R₁═NH₂, R₂ to R₇═H, R₈═SO₃H is the same    meaning as hereinbefore defined;

-   161. A compound in which Z═R₁═NH₂, R₂ to R₇═H, R₈═OSO₃H is the same    meaning as hereinbefore defined;

-   162. A compound in which Z═NH₂, R₂═NHSO₃H, R₁ and R₃ to R₈═H is the    same meaning as hereinbefore defined;

-   163. A compound in which Z═NH₂, R₂ to R₈═H, R₁═CH₂SO₃H is the same    meaning as hereinbefore defined;

-   164. A compound in which Z═NH₂, R₂ to R₈═H, R₁═CH₂OSO₃H is the same    meaning as hereinbefore defined;

-   165. A compound in which Z═NH₂, R₂ to R₈═H, R₁═SO₃H is the same    meaning as hereinbefore defined;

-   166. A compound in which Z═NH₂, R₂ to R₈═H, R₁═OSO₃H is the same    meaning as hereinbefore defined;

-   167. A compound in which Z═R₂═NH₂, R₃ to R₈═H, R₁═SO₃H is the same    meaning as hereinbefore defined;

-   168. A compound in which Z═R₂═NH₂, R₃ to R₈═H, R₁═OSO₃H is the same    meaning as hereinbefore defined;

-   169. A compound in which Z═R₂═NH₂, R₁, R₄ to R₈═H, R₃═SO₃H is the    same meaning as hereinbefore defined;

-   170. A compound in which Z═R₂═NH₂, R₁, R₄ to R₈═H, R₃═OSO₃H is the    same meaning as hereinbefore defined;

-   171. A compound in which Z═R₂═NH₂, R₁═R₃═H, R₅ to R₈═H, R₄═SO₃H is    the same meaning as hereinbefore defined;

-   172. A compound in which Z═R₂═NH₂, R₁═R₃═H, R₅ to R₈═H, R₄═OSO₃H is    the same meaning as hereinbefore defined;

-   173. A compound in which Z═R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H, R₅═SO₃H    is the same meaning as hereinbefore defined;

-   174. A compound in which Z═R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H, R₅═OSO₃H    is the same meaning as hereinbefore defined;

-   175. A compound in which Z═R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,    R₆═SO₃H is the same meaning as hereinbefore defined;

-   176. A compound in which Z═R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,    R₆═OSO₃H is the same meaning as hereinbefore defined;

-   177. A compound in which Z═R₂═NH₂, R₁═R₈═H, R₃ to R₆═H, R₇═SO₃H is    the same meaning as hereinbefore defined;

-   178. A compound in which Z═R₂═NH₂, R₁═R₈═H, R₃ to R₆═H, R₇═OSO₃H is    the same meaning as hereinbefore defined;

-   179. A compound in which Z═R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═SO₃H is the    same meaning as hereinbefore defined;

-   180. A compound in which Z═R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═OSO₃H is the    same meaning as hereinbefore defined.    C) The osteoclast inhibitors also contained different divalent metal    ions such as Mg, Ca and Zn. The composition consisted of varying    amounts of the above acid amino acid/dicarboxylic acid derivatives    and their pharmaceutically acceptable salts. Non toxic salts of the    present invention are contained all pharmaceutically acceptable    salts, for example, general salts, acid addition salt, hydrate    salts.

The compounds of the formulae (Ia), (Ib) and (Ic) of the presentinvention may be converted into the corresponding salts. Non toxic andwater soluble salts are preferable. Suitable salts for example are asfollows:

-   -   Salts of alkaline earth metals (Mg, Ca etc)    -   Ammonium Salts    -   Salts of pharmaceutically acceptable organic amines (tetramethyl        ammonium, triethyl amine, methyl amine, cyclopentyl amine,        benzylamine, phenethylamine, piperidine, monoethanolamine,        diethanolamine, tris(hydroxymethyl)amine, lysine, arginine,        N-methyl glucamine, etc.        d) In the compound of the present invention of the formulae        (Ia), (Ib) and (Ic) the following non toxic derivatives thereof        are preferable:    -   1. L-Aspartic acid, N-Sulfonic acid    -   2. L-Aspartic acid, 2β-sulfonic acid    -   3. L-Aspartic acid, 2β-sulfate    -   4. L-aspartic acid, 3α-sulfonic acid    -   5. L-aspartic acid, 3α-sulfate    -   6. L-aspartic acid, 3β-sulfonic acid    -   7. L-aspartic acid, 3β-sulfate    -   8. 2α,3-dicarboxy, propane-1-sulfonic acid    -   9. 2α,3-dicarboxy, propane-1-sulfate    -   10. 1α,2-carboxy ethane sulfonic acid    -   11. 1α,2-carboxy ethane sulfate    -   12. D-aspartic acid, N-sulfonic acid    -   13. 2β,3-carboxy, propane-1-sulfonic acid    -   14. 2β,3-carboxy, propane-1-sulfate    -   15. 1β,2-carboxy ethane-1-sulfonic acid    -   16. 1β,2-carboxy ethane-1-sulfate    -   17. D-aspartic acid, 2α-sulfonic acid    -   18. D-aspartic acid, 2α-sulfonic acid    -   19. D-Aspartic acid, 3α-sulfonic acid    -   20. D-Aspartic acid, 3α-sulfate    -   21. D-Aspartic acid, 3β-sulfonic acid    -   22. D-aspartic acid, 3β-sulfate    -   23. L-asparagine, N-sulfonic acid    -   24. 2α-carboxy, 3-carboxamido, propane-1-sulfonic acid    -   25. 2α-carboxy, 3-carboxamido, propane-1-sulfate    -   26. 1α-carboxy, 2-carboxamido, ethane sulfonic acid    -   27. 1α-carboxy, 2-carboxamido, ethane sulfate    -   28. L-asparagine, 2β-sulfonic acid    -   29. -asparagine, 2β-sulfate    -   30. L-asparagine, 3α-sulfonic acid    -   31. L-asparagine, 3α-sulfate    -   32. L-asparagine, 3β-sulfonic acid    -   33. L-asparagine, 3β-sulfate    -   34. D-asparagine, N-sulfonic acid    -   35. 2β-carboxy, 3-carboxamido, propane-1-sulfonic acid    -   36. 2β-carboxy, 3-carboxamido, propane-1-sulfate    -   37. 1β-carboxy, 2-carboxamido, ethane sulfonic acid]    -   38. 1β-carboxy, 2-carboxamido, ethane sulfate    -   39. D-asparagine, 2α-sulfonic acid    -   40. D-asparagine, 2α-sulfate    -   41. D-asparagine, 3α-sulfonic acid    -   42. D-asparagine, 3α-sulfate    -   43. D-asparagine, 3β-sulfonic acid    -   44. D-asparagine, 3β-sulfate    -   45. L-glutamic acid, N-sulfonic acid    -   46. 2α,4-dicarboxy, butane-1-sulfonic acid    -   47. 2α,4-dicarboxy, butane-1-sulfate    -   48. 1α,3-dicarboxy, propane sulfonic acid    -   49. 1α,3-dicarboxy, propane sulfate    -   50. 1β,3-dicarboxy, propane sulfate    -   51. 1β,3-dicarboxy, propane sulfonic acid    -   52. L-glutamic acid, 2β-sulfonic acid    -   53. L-glutamic acid, 2β-sulfate    -   54. L-glutamic acid, 3α-sulfonic acid    -   55. L-glutamic acid, 3α-sulfate    -   56. L-glutamic acid, 3β-sulfonic acid    -   57. L-glutamic acid, 3β-sulfate    -   58. L-glutamic acid, 4α-sulfonic acid    -   59. L-glutamic acid, 4α-sulfate    -   60. L-glutamic acid, 4β-sulfonic acid    -   61. L-glutamic acid, 4β-sulfate    -   62. D-glutamic acid, N-sulfonic acid    -   63. 2β,4-dicarboxy, butane-1-sulfonic acid    -   64. 2β,4-dicarboxy, butane-1-sulfate    -   65. D-glutamic acid, 2α-sulfonic acid    -   66. D-glutamic acid, 2α-sulfate    -   67. D-glutamic acid, 3α-sulfonic acid    -   68. D-glutamic acid, 3α-sulfate    -   69. D-glutamic acid, 3β-sulfonic acid    -   70. D-glutamic acid, 3β-sulfate    -   71. D-glutamic acid, 4α-sulfonic acid    -   72. D-glutamic acid, 4α-sulfate    -   73. D-glutamic acid, 4β-sulfonic acid    -   74. D-glutamic acid, 4β-sulfate    -   75. L-glutamine, N-sulfonic acid    -   76. L-glutamine, 2β-sulfonic acid    -   77. L-glutamine, 2β-sulfate    -   78. L-glutamine, 3α-sulfonic acid    -   79. L-glutamine, 3α-sulfate    -   80. L-glutamine, 3β-sulfonic acid    -   81. L-glutamine, 3β-sulfate    -   82. L-glutamine, 4α-sulfonic acid    -   83. L-glutamine, 4α-sulfate    -   84. L-glutamine, 4β-sulfonic acid    -   85. L-glutamine, 4β-sulfate    -   86. 2α-carboxy, 4-carboxamido, butane-1-sulfonic acid    -   87. 2α-carboxy, 4-carboxamido, butane-1-sulfate    -   88. 1α-carboxy, 3-carboxamido, propane-1-sulfonic acid    -   89. 1α-carboxy, 3-carboxamido, propane-1-sulfate    -   90. 1β-carboxy, 3-carboxamido, propane-1-sulfate    -   91. 1β-carboxy, 3-carboxamido, propane-1-sulfonic acid    -   92. D-glutamine, N-sulfonic acid    -   93. 2β-carboxy, 4-carboxamido, butane-1-sulfonic acid    -   94. 2β-carboxy, 4-carboxamido, butane-1-sulfate    -   95. D-glutamine, 2α-sulfonic acid    -   96. D-glutamine, 2α-sulfate    -   97. D-glutamine, 3α-sulfonic acid    -   98. D-glutamine, 3α-sulfate    -   99. D-glutamine, 3β-sulfonic acid    -   100. D-glutamine, 3β-sulfate    -   101. D-glutamine, 4α-sulfonic acid    -   102. D-glutamine, 4α-sulfate    -   103. D-glutamine, 4β-sulfonic acid    -   104. D-glutamine, 4β-sulfate    -   105. L-homoglutamic acid, N-sulfonic acid    -   106. Pentane-2α,5-dicarboxy-1-sulfonic acid    -   107. Pentane-2α,5-dicarboxy-1-sulfate    -   108. Butane-1α,4-dicarboxy-1-sulfonic acid    -   109. Butane-1α,4-dicarboxy-1-sulfate    -   110. L-homoglutamic acid, 2β-sulfonic acid    -   111. L-homoglutamic acid, 2β-sulfate    -   112. L-homoglutamic acid, 3α-sulfonic acid    -   113. L-homoglutamic acid, 3α-sulfate    -   114. L-homoglutamic acid, 3β-sulfonic acid    -   115. L-homoglutamic acid, 3β-sulfate    -   116. L-homoglutamic acid, 4α-sulfonic acid    -   117. L-homoglutamic acid, 4α-sulfate    -   118. L-homoglutamic acid, 4β-sulfonic acid    -   119. L-homoglutamic acid, 4β-sulfate    -   120. L-homoglutamic acid, 5α-sulfonic acid    -   121. L-homoglutamic acid, 5α-sulfate    -   122. L-homoglutamic acid, 5β-sulfonic acid    -   123. L-homoglutamic acid, 5β-sulfate    -   124. D-homoglutamic acid, N-sulfonic acid    -   125. Pentane-2β,5-dicarboxy-1-sulfonic acid    -   126. Pentane-2β,5-dicarboxy-1-sulfate    -   127. Butane-1β,4-dicarboxy-1-sulfonic acid    -   128. Butane-1β,4-dicarboxy-1-sulfate    -   129. D-homoglutamic acid, 2α-sulfonic acid    -   130. D-homoglutamic acid, 2α-sulfate    -   131. D-homoglutamic acid, 3α-sulfonic acid    -   132. D-homoglutamic acid, 3α-sulfate    -   133. D-homoglutamic acid, 3β-sulfonic acid    -   134. D-homoglutamic acid, 3β-sulfate    -   135. D-homoglutamic acid, 4α-sulfonic acid    -   136. D-homoglutamic acid, 4α-sulfate    -   137. D-homoglutamic acid, 4β-sulfonic acid    -   138. D-homoglutamic acid, 4β-sulfate    -   139. D-homoglutamic acid, 5α-sulfonic acid    -   140. D-homoglutamic acid, 5α-sulfate    -   141. D-homoglutamic acid, 5β-sulfonic acid    -   142. D-homoglutamic acid, 5β-sulfate    -   143. L-homoglutamine, N-sulfonic acid    -   144. Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid    -   145. Pentane-2α-carboxy, 5-carboxamido-1-sulfate    -   146. Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid    -   147. Butane-1α-carboxy, 4-carboxamido-1-sulfate    -   148. L-homoglutamine, 2β-sulfonic acid    -   149. L-homoglutamine, 2β-sulfate    -   150. L-homoglutamine, 3α-sulfonic acid    -   151. L-homoglutamine, 3α-sulfate    -   152. L-homoglutamine, 3β-sulfonic acid    -   153. L-homoglutamine, 3β-sulfate    -   154. L-homoglutamine, 4α-sulfonic acid    -   155. L-homoglutamine, 4α-sulfate    -   156. L-homoglutamine, 4β-sulfonic acid    -   157. L-homoglutamine, 4β-sulfate    -   158. L-homoglutamine, 5α-sulfonic acid    -   159. L-homoglutamine, 5α-sulfate    -   160. L-homoglutamine, 5β-sulfonic acid    -   161. L-homoglutamine, 5β-sulfate    -   162. D-homoglutamine, N-sulfonic acid    -   163. Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid    -   164. Pentane-2β-carboxy, 5-carboxamido-1-sulfate    -   165. Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid    -   166. Butane-1β-carboxy, 4-carboxamido-1-sulfate    -   167. D-homoglutamine, 2α-sulfonic acid    -   168. D-homoglutamine, 2α-sulfate    -   169. D-homoglutamine, 3α-sulfonic acid    -   170. D-homoglutamine, 3α-sulfate    -   171. D-homoglutamine, 3β-sulfonic acid    -   172. D-homoglutamine, 3β-sulfate    -   173. D-homoglutamine, 4α-sulfonic acid    -   174. D-homoglutamine, 4α-sulfate    -   175. D-homoglutamine, 4β-sulfonic acid    -   176. D-homoglutamine, 4β-sulfate    -   177. D-homoglutamine, 5α-sulfonic acid    -   178. D-homoglutamine, 5α-sulfate    -   179. D-homoglutamine, 5β-sulfonic acid    -   180. D-homoglutamine, 5β-sulfate.        e) a process for the preparation of sulfonic acid/sulfate        derivatives of the formula (Ia) and non-toxic salts thereof:

-   1. A compound wherein Z═OH, R₁═NHSO₃H, R₂═R₃═R₄═H;

-   2. A compound wherein Z═OH, R₁═NH₂, R₃═R₄═H, R₂═SO₃H;

-   3. A compound in which Z═OH, R₁═NH₂, R₃═R₄═H, R₂═OSO₃H;

-   4. A compound in which Z═OH, R₁═NH₂, R₂═R₄═H, R₃═SO₃H;

-   5. A compound in which Z═OH, R₁═NH₂, R₂═R₄═H, R₃═OSO₃H;

-   6. A compound in which Z═OH, R₁═NH₂, R₂═R₃═H, R₄═SO₃H;

-   7. A compound in which Z═OH, R₁═NH₂, R₂═R₃═H, R₄═OSO₃H;

-   8. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═CH₂SO₃H;

-   9. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═CH₂OSO₃H;

-   10. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═SO₃H;

-   11. A compound in which Z═OH, R₁═R₃═R₄═H, R₂═OSO₃H;

-   12. A compound in which Z═OH, R₂═NHSO₃H, R₁═R₃═R₄═H;

-   13. A compound in which Z═OH, R₂═H, R₁═CH₂SO₃H;

-   14. A compound in which Z═OH, R₂═H, R₁═CH₂OSO₃H;

-   15. A compound in which Z═OH, R₂═H, R₁═SO₃H;

-   16. A compound in which Z═OH, R₂═H, R₁═OSO₃H;

-   17. A compound in which Z═OH, R₂═NH₂, R₃═R₄═H, R₁═SO₃H;

-   18. A compound in which Z═OH, R₂═NH₂, R₃═R₄═H, R₁═SO₃H;

-   19. A compound in which Z═OH, R₂═NH₂, R₁═R₄═H, R₃═SO₃H;

-   20. A compound wherein Z═OH, R₂═NH₂, R═R₄═H, R₃═OSO₃H;

-   21. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═H, R₄═SO₃H;

-   22. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═H, R₄═OSO₃H;

-   23. A compound wherein R₁═NHSO₃H, R₂═R₃═R₄═H;

-   24. A compound wherein Z═NH₂, R₁═H, R₂═CH₂SO₃H;

-   25. A compound wherein Z═NH₂, R₁═H, R₂═CH₂OSO₃H;

-   26. A compound wherein Z═NH₂, R₁═H, R₂═SO₃H;

-   27. A compound wherein Z═NH₂, R₁═H, R₂═OSO₃H;

-   28. A compound wherein Z═R₁═NH₂, R₂═R₄═H, R₂═SO₃H;

-   29. A compound wherein Z═R₁═NH₂, R₂═R₄═H, R₃═OSO₃H;

-   30. A compound wherein Z═R₁═NH₂, R₂═R₄═H, R₃═SO₃H;

-   31. A compound wherein Z═R₁═NH₂, R₂═R₄═H, R₃═OSO₃H;

-   32. A compound wherein Z═R₁═NH₂, R₂═R₃═H, R₄═SO₃H;

-   33. A compound wherein Z═R₁═NH₂, R₂═R₃═H, R₄═OSO₃H;

-   34. A compound wherein Z═NH₂, R₂═NHSO₃H, R₁═R₃═R₄═H;

-   35. A compound wherein Z═NH₂, R₂ to R₄═H, R₁═CH₂SO₃H;

-   36. A compound wherein Z═NH₂, R₂ to R₄═H, R₁═CH₂SO₃H;

-   37. A compound wherein Z═OH, R₂ to R₄═H, R₁═SO₃H;

-   38. A compound wherein Z═OH, R₂ to R₄═H, R₁═OSO₃H;

-   39. A compound wherein Z═R₂═NH₂, R₃═R₄═H, R₁═SO₃H;

-   40. A compound wherein Z═R₂═NH₂, R₃═R₄═H, R₁═OSO₃H;

-   41. A compound wherein Z═R₂═NH₂, R₁═R₄═H, R₃═SO₃H;

-   42. A compound wherein Z═R₂═NH₂, R₁═R₄═H, R₃═OSO₃H;

-   43. A compound wherein Z═R₂═NH₂, R₁═R₃═H, R₄═SO₃H;

-   44. A compound wherein Z═R₂═NH₂, R₁═R₃═H, R₄═OSO₃H;    f) a process for the preparation of sulfonic acid/sulfate    derivatives of the formula (Ib) and non-toxic salts thereof:

-   1. A compound wherein Z═OH, R₁═NHSO₃H, R₂═R₃═R₄═R₅═R₆═H;

-   2. A compound wherein Z═OH, R₁, R₃ to R₆═H, R₂═CH₂SO₃H;

-   3. A compound wherein Z═OH, R₁, R₃ to R₆═H, R₂═CH₂OSO₃H;

-   4. A compound wherein Z═OH, R₁, R₃ to R₆═H, R₂═SO₃H;

-   5. A compound wherein Z═OH, R₁, R₃ to R₆═H, R₂═OSO₃H;

-   6. A compound wherein Z═OH, R₂ to R₆═H, R₁═OSO₃H;

-   7. A compound wherein Z═OH, R₂ to R₆═H, R₁═SO₃H;

-   8. A compound wherein Z═OH, R₁═NH₂, R₃ to R₆═H, R₂═SO₃H;

-   9. A compound wherein Z═OH, R₁═NH₂, R₃ to R₆═H, R₂═OSO₃H;

-   10. A compound wherein Z═OH, R₁═NH₂, R₂═H, R₄ to R₆═H, R₃═SO₃H;

-   11. A compound wherein Z═OH, R₁═NH₂, R₂═H, R₄ to R₆═H, R₃═OSO₃H;

-   12. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═SO₃H;

-   13. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═OSO₃H;

-   14. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═SO₃H;

-   15. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═OSO₃H;

-   16. A compound wherein Z═OH, R₁═NH₂, R₂ to R₅═H, R₆═SO₃H;

-   17. A compound wherein Z═OH, R₁═NH₂, R₂ to R₅═H, R₆═OSO₃H;

-   18. A compound wherein Z═OH, R₂═NHSO₃H, R₁, R₃ to R₆═H;

-   19. A compound wherein Z═OH, R₂ to R₆═H, R₁═CH₂SO₃H;

-   20. A compound wherein Z═OH, R₂ to R₆═H, R₁═CH₂OSO₃H;

-   21. A compound wherein Z═OH, R₂═NH₂, R₃ to R₆H, R₁═SO₃H;

-   22. A compound wherein Z═OH, R₂═NH₂, R₃ to R₆H, R₁═OSO₃H;

-   23. A compound wherein Z═OH, R₂═NH₂, R₁, R₄ to R₆H, R₃═SO₃H;

-   24. A compound wherein Z═OH, R₂═NH₂, R₁, R₄ to R₆H, R₃═OSO₃H;

-   25. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═SO₃H;

-   26. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═OSO₃H;

-   27. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═SO₃H;

-   28. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═OSO₃H;

-   29. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₄═R₅═H, &═SO₃H;

-   30. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═OSO₃H;

-   31. A compound wherein Z═NH₂, R₁═NHSO₃H, R₂ to R₆═H;

-   32. A compound wherein Z═R₁═NH₂, R₃ to R₆═H, R₂═SO₃H;

-   33. A compound wherein Z═R₁═NH₂, R₃ to R₆═H, R₂═OSO₃H;

-   34. A compound wherein Z═R₁═NH₂, R₂═H, R₃ to R₆═H, R₃═SO₃H;

-   35. A compound wherein Z═R₁═NH₂, R₂═H, R₃ to R₆═H, R₃═OSO₃H;

-   36. A compound wherein Z═R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═SO₃H;

-   37. A compound wherein Z═R₁═NH₂, R₂═R₃═R₅═R₆═H, R₄═OSO₃H;

-   38. A compound wherein Z═R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═SO₃H;

-   39. A compound wherein Z═R₁═NH₂, R₂═R₃═R₄═R₆═H, R₅═OSO₃H;

-   40. A compound wherein Z═R₁═NH₂, R₂ to R₅═H, R₆═SO₃H;

-   41. A compound wherein Z═R₁═NH₂, R₂ to R₅═H, R₆═OSO₃H;

-   42. A compound wherein Z═NH₂, R₁, R₃ to R₆═H, R₂═CH₂SO₃H;

-   43. A compound wherein Z═NH₂, R₁, R₃ to R₆═H, R₂═CH₂OSO₃H;

-   44. A compound wherein Z═NH₂, R₁, R₃ to R₆═H, R₂═SO₃H;

-   45. A compound wherein Z═NH₂, R₁, R₃ to R₆═H, R₂═OSO₃H;

-   46. A compound wherein Z═NH₂, R₂ to R₆═H, R₁═OSO₃H;

-   47. A compound wherein Z═NH₂, R₂ to R₆═H, R₁═SO₃H;

-   48. A compound wherein Z═NH₂, R₂═NHSO₃H; R₁═H, R₃ to R₆═H;

-   49. A compound wherein Z═NH₂, R₂ to R₆═H, R₁═CH₂SO₃H;

-   50. A compound wherein Z═NH₂, R₂ to R₆═H, R₁═CH₂OSO₃H;

-   51. A compound wherein Z═NH₂, R₂═NH₂, R₃ to R₆═H, R₁═SO₃H;

-   52. A compound wherein Z═NH₂, R₂═NH₂, R₃ to R₆═H, R₁═OSO₃H;

-   53. A compound wherein Z═NH₂, R₂═NH₂, R₁, R₄ to R₆H, R₃═SO₃H;

-   54. A compound wherein Z═R₂═NH₂, R₁, R₄ to R₆H, R₃═OSO₃H;

-   55. A compound wherein Z═R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═SO₃H;

-   56. A compound wherein Z═R₂═NH₂, R₁═R₃═R₅═R₆═H, R₄═OSO₃H;

-   57. A compound wherein Z═R₂═NH₂, R₁═R₃═P4═R₆═H, R₅═SO₃H;

-   58. A compound wherein Z═R₂═NH₂, R₁═R₃═R₄═R₆═H, R₅═OSO₃H;

-   59. A compound wherein Z═R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═SO₃H;

-   60. A compound wherein Z═R₂═NH₂, R₁═R₃═R₄═R₅═H, R₆═OSO₃H;    g) a process for the preparation of sulfonic acid/sulfate    derivatives of the formula (Ic) and non-toxic salts thereof:

-   1. A compound wherein Z═OH, R₁═NHSO₃H, R₂ to R₈═H;

-   2. A compound wherein Z═OH, R₁, R₃ to R₈═H, R₂═CH₂SO₃H;

-   3. A compound wherein Z═OH, R₁, R₃ to R₈═H, R₂═CH₂OSO₃H;

-   4. A compound wherein Z═OH, R₁, R₃ to R₈═H, R₂═SO₃H;

-   5. A compound wherein Z═OH, R₁, R₃ to R₈═H, R₂═OSO₃H;

-   6. A compound wherein Z═OH, R₁═NH₂, R₃ to R₈═H, R₂═SO₃H;

-   7. A compound wherein Z═OH, R₁═NH₂, R₃ to R₈═H, R₂═OSO₃1H;

-   8. A compound wherein Z═OH, R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═SO₃H;

-   9. A compound wherein Z═OH, R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═OSO₃H;

-   10. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═H, R₅ to R₈═H, R₄═SO₃H;

-   11. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═H, R₅ to R₈═H, R₄═OSO₃H;

-   12. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H,    R₅═SO₃H;

-   13. A compound wherein Z═OH, R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H,    R₅═OSO₃H;

-   14. A compound wherein Z═OH, R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═SO₃H;

-   15. A compound wherein Z═OH, R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═OSO₃H;

-   16. A compound wherein Z═OH, R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═SO₃H

-   17. A compound wherein Z═OH, R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═OSO₃H;

-   18. A compound wherein Z═OH, R₁═NH₂, R₂ to R₇═H, R₈═SO₃H;

-   19. A compound wherein Z═OH, R₁═NH₂, R₂ to R₇═H, R₈═OSO₃H;

-   20. A compound wherein Z═OH, R₂═NHSO₃H, R₁, R₃ to R₈═H;

-   21. A compound wherein Z═OH, R₂ to R₈═H, R₁═CH₂SO₃H;

-   22. A compound wherein Z═OH, R₂ to R₈═H, R₁═CH₂OSO₃H;

-   23. A compound wherein Z═OH, R₂ to R₈═H, R₁═SO₃H;

-   24. A compound wherein Z═OH, R₂ to R₈═H, R₁═OSO₃H;

-   25. A compound wherein Z═OH, R₂═NH₂, R₃ to R₈═H, R₁═SO₃H;

-   26. A compound wherein Z═OH, R₂═NH₂, R₃ to R₈═H, R₁═OSO₃H;

-   27. A compound wherein Z═OH, R₂═NH₂, R₁, R₄ to R₈═H, R₃═SO₃H;

-   28. A compound wherein Z═OH, R₂═NH₂, R₁, R₄ to R₈═H, R₃═OSO₃H;

-   29. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═H, R₅ to R₈═H, R₄═SO₃H;

-   30. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═H, R₅ to R₈═H, R₄═OSO₃H;

-   31. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H,    R₅═SO₃H;

-   32. A compound wherein Z═OH, R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H,    R₅═OSO₃H;

-   33. A compound wherein Z═OH, R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,    R₆═SO₃H;

-   34. A compound wherein Z═OH, R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,    R₆═OSO₃H;

-   35. A compound wherein Z═OH, R₂═NH₂, R═R₈═H, R₃ to R₆═H, R₇═SO₃H;

-   36. A compound wherein Z═OH, R₂═NH₂, R₁═R₈═H, R₃ to R₆═H, R₇═OSO₃H;

-   37. A compound wherein Z═OH, R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═SO₃H;

-   38. A compound wherein Z═OH, R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═OSO₃H;

-   39. A compound wherein Z═NH₂, R₁═NHSO₃H, R₂ to R₈═H;

-   40. A compound wherein Z═NH₂, R₁ and R₃ to R₈═H, R₂═CH₂SO₃H;

-   41. A compound wherein Z═NH₂, R₁ and R₃ to R₈═H, R₂═CH₂OSO₃H;

-   42. A compound wherein Z═NH₂, R₁ and R₃ to R₈═H, R₂═SO₃H;

-   43. A compound wherein Z═NH₂, R₁ and R₃ to R₈═H, R₂═OSO₃H;

-   44. A compound wherein Z═R₁═NH₂, R₃ to R₈═H, R₂═SO₃H;

-   45. A compound wherein Z═R₁═NH₂, R₃ to R₈═H, R₂═OSO₃H;

-   46. A compound wherein Z═R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═SO₃H;

-   47. A compound wherein Z═R₁═NH₂, R₂═H, R₄ to R₈═H, R₃═OSO₃H;

-   48. A compound wherein Z═R₁═NH₂, R₂═R₃═H, R₅ to R₈═H, R₄═SO₃H;

-   49. A compound wherein Z═R₁═NH₂, R₂═R₃═H, R₅ to R₈═H, R₄═OSO₃H;

-   50. A compound wherein Z═R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H, R₅═SO₃H;

-   51. A compound wherein Z═R₁═NH₂, R₂═R₃═R₄═H, R₆ to R₈═H, R₅═OSO₃H;

-   52. A compound wherein Z═R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═SO₃H;

-   53. A compound wherein Z═R₁═NH₂, R₂═R₅═H, R₇═R₈═H, R₆═OSO₃H;

-   54. A compound wherein Z═R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═SO₃H;

-   55. A compound wherein Z═R₁═NH₂, R₂ to R₆═H, R₈═H, R₇═OSO₃H;

-   56. A compound wherein Z═R₁═NH₂, R₂ to R₇═H, R₈═SO₃H;

-   57. A compound wherein Z═R₁═NH₂, R₂ to R₇═H, R₈═OSO₃H;

-   58. A compound wherein Z═NH₂, R₂═NHSO₃H, R₁ and R₃ to R₈═H;

-   59. A compound wherein Z═NH₂, R₂ to R₈═H, R₁═CH₂SO₃H;

-   60. A compound wherein Z═NH₂, R₂ to R₈═H, R₁═CH₂OSO₃H;

-   61. A compound wherein Z═NH₂, R₂ to R₈═H, R₁═SO₃H;

-   62. A compound wherein Z═NH₂, R₂ to R₈═H, R₁═OSO₃H;

-   63. A compound wherein Z═R₂═NH₂, R₃ to R₈═H, R₁═SO₃H;

-   64. A compound wherein Z═R₂═NH₂, R₃ to R₈═H, R₁═OSO₃H;

-   65. A compound wherein Z═R₂═NH₂, R₁, R₄ to R₈═H, R₃═SO₃H;

-   66. A compound wherein Z═R₂═NH₂, R₁, R₄ to R₈═H, R₃═OSO₃H;

-   67. A compound wherein Z═R₂═NH₂, R₁═R₃═H, R₅ to R₈═H, R₄═SO₃H;

-   68. A compound wherein Z═R₂═NH₂, R₁═R₃═H, R₅ to R₈═H, R₄═OSO₃H;

-   69. A compound wherein Z═R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H, R₅═SO₃H;

-   70. A compound wherein Z═R₂═NH₂, R₁═R₃═R₄═H, R₆ to R₈═H, R₅═OSO₃H;

-   71. A compound wherein Z═R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H, R₆═SO₃H;

-   72. A compound wherein Z═R₂═NH₂, R₁═H, R₃ to R₅═H, R₇═R₈═H,    R₆═OSO₃H;

-   73. A compound wherein Z═R₂═NH₂, R₁═R₈═H, R₃ to R₆═H, R₇═SO₃H;

-   74. A compound wherein Z═R₂═NH₂, R₁═R₈═H, R₃ to R₆═H, R₇═OSO₃H;

-   75. A compound wherein Z═R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═SO₃H;

-   76. A compound wherein Z═R₂═NH₂, R₁═H, R₃ to R₇═H, R₈═OSO₃H.    h) In the compound of the present invention of the formula (Ia)    wherein the compound is selected from the group consisting of    aspartic acid, asparagine and corresponding de-amino analogs:    -   1. L-Aspartic acid, N-Sulfonic acid    -   2. L-Aspartic acid, 2β-sulfonic acid    -   3. L-Aspartic acid, 2β-sulfate    -   4. L-aspartic acid, 3α-sulfonic acid    -   5. L-aspartic acid, 3α-sulfate    -   6. L-aspartic acid, 3β-sulfonic acid    -   7. L-aspartic acid, 3β-sulfate    -   8. 2α,3-dicarboxy, propane-1-sulfonic acid    -   9. 2α,3-dicarboxy, propane-1-sulfate    -   10. 1α,2-carboxy ethane sulfonic acid    -   11. 1α,2-carboxy ethane sulfate    -   12. D-aspartic acid, N-sulfonic acid    -   13. 2β,3-carboxy, propane-1-sulfonic acid    -   14. 2β,3-carboxy, propane-1-sulfate    -   15. 1β,2-carboxy ethane-1-sulfonic acid    -   16. 1β,2-carboxy ethane-1-sulfate    -   17. D-aspartic acid, 2α-sulfonic acid    -   18. D-aspartic acid, 2α-sulfonic acid    -   19. D-Aspartic acid, 3α-sulfonic acid    -   20. D-Aspartic acid, 3α-sulfate    -   21. D-Aspartic acid, 3β-sulfonic acid    -   22. D-aspartic acid, 3β-sulfate    -   23. L-asparagine, N-sulfonic acid    -   24. 2α-carboxy, 3-carboxamido, propane-1-sulfonic acid    -   25. 2α-carboxy, 3-carboxamido, propane-1-sulfate    -   26. 1α-carboxy, 2-carboxamido, ethane sulfonic acid    -   27. 1α-carboxy, 2-carboxamido, ethane sulfate    -   28. L-asparagine, 2β-sulfonic acid    -   29. -asparagine, 2β-sulfate    -   30. L-asparagine, 3α-sulfonic acid    -   31. L-asparagine, 3α-sulfate    -   32. L-asparagine, 3β-sulfonic acid    -   33. L-asparagine, 3β-sulfate    -   34. D-asparagine, N-sulfonic acid    -   35. 2β-carboxy, 3-carboxamido, propane-1-sulfonic acid    -   36. 2β-carboxy, 3-carboxamido, propane-1-sulfate    -   37. 1β-carboxy, 2-carboxamido, ethane sulfonic acid]    -   38. 1β-carboxy, 2-carboxamido, ethane sulfate    -   39. D-asparagine, 2α-sulfonic acid    -   40. D-asparagine, 2α-sulfate    -   41. D-asparagine, 3α-sulfonic acid    -   42. D-asparagine, 3α-sulfate    -   43. D-asparagine, 3β-sulfonic acid    -   44. D-asparagine, 3β-sulfate.        i) In the compound of the present invention of the formula (Ib)        wherein the compound is selected from the group consisting of        glutamic acid, glutamine and corresponding de-amino analogs:

-   1. 1 L-glutamic acid, N-sulfonic acid

-   2. 2α,4-dicarboxy, butane-1-sulfonic acid

-   3. 2α,4-dicarboxy, butane-1-sulfate

-   4. 1α,3-dicarboxy, propane sulfonic acid

-   5. 1α,3-dicarboxy, propane sulfate

-   6. 1β,3-dicarboxy, propane sulfate

-   7. 1β,3-dicarboxy, propane sulfonic acid

-   8. L-glutamic acid, 2β-sulfonic acid

-   9. L-glutamic acid, 2β-sulfate

-   10. L-glutamic acid, 3α-sulfonic acid

-   11. L-glutamic acid, 3α-sulfate

-   12. L-glutamic acid, 3β-sulfonic acid

-   13. L-glutamic acid, 3β-sulfate

-   14. L-glutamic acid, 4α-sulfonic acid

-   15. L-glutamic acid, 4α-sulfate

-   16. L-glutamic acid, 4β-sulfonic acid

-   17. L-glutamic acid, 4β-sulfate

-   18. D-glutamic acid, N-sulfonic acid

-   19. 2β,4-dicarboxy, butane-1-sulfonic acid

-   20. 2β,4-dicarboxy, butane-1-sulfate

-   21. D-glutamic acid, 2α-sulfonic acid

-   22. D-glutamic acid, 2α-sulfate

-   23. D-glutamic acid, 3α-sulfonic acid

-   24. D-glutamic acid, 3α-sulfate

-   25. D-glutamic acid, 3β-sulfonic acid

-   26. D-glutamic acid, 3β-sulfate

-   27. D-glutamic acid, 4α-sulfonic acid

-   28. D-glutamic acid, 4α-sulfate

-   29. D-glutamic acid, 4β-sulfonic acid

-   30. D-glutamic acid, 4β-sulfate

-   31. L-glutamine, N-sulfonic acid

-   32. L-glutamine, 2β-sulfonic acid

-   33. L-glutamine, 2β-sulfate

-   34. L-glutamine, 3α-sulfonic acid

-   35. L-glutamine, 3α-sulfate

-   36. L-glutamine, 3β-sulfonic acid

-   37. L-glutamine, 3β-sulfate

-   38. L-glutamine, 4α-sulfonic acid

-   39. L-glutamine, 4α-sulfate

-   40. L-glutamine, 4β-sulfonic acid

-   41. L-glutamine, 4β-sulfate

-   42. 2α-carboxy, 4-carboxamido, butane-1-sulfonic acid

-   43. 2α-carboxy, 4-carboxamido, butane-1-sulfate

-   44. 1α-carboxy, 3-carboxamido, propane-1-sulfonic acid

-   45. 1α-carboxy, 3-carboxamido, propane-1-sulfate

-   46. 1β-carboxy, 3-carboxamido, propane-1-sulfate

-   47. 1β-carboxy, 3-carboxamido, propane-1-sulfonic acid

-   48. D-glutamine, N-sulfonic acid

-   49. 2β-carboxy, 4-carboxamido, butane-1-sulfonic acid

-   50. 2β-carboxy, 4-carboxamido, butane-1-sulfate

-   51. D-glutamine, 2α-sulfonic acid

-   52. D-glutamine, 2α-sulfate

-   53. D-glutamine, 3α-sulfonic acid

-   54. D-glutamine, 3α-sulfate

-   55. D-glutamine, 3β-sulfonic acid

-   56. D-glutamine, 3β-sulfate

-   57. D-glutamine, 4α-sulfonic acid

-   58. D-glutamine, 4α-sulfate

-   59. D-glutamine, 4β-sulfonic acid

-   60. D-glutamine, 4β-sulfate    j) In the compound of the present invention of the formula (Ic)    wherein the compound is selected from the group consisting of    homoglutamic acid, homoglutamine and corresponding de-amino analogs:

-   1. L-homoglutamic acid, N-sulfonic acid

-   2. Pentane-2α,5-dicarboxy-1-sulfonic acid

-   3. Pentane-2α,5-dicarboxy-1-sulfate

-   4. Butane-1α,4-dicarboxy-1-sulfonic acid

-   5. Butane-1α,4-dicarboxy-1-sulfate

-   6. L-homoglutamic acid, 2β-sulfonic acid

-   7. L-homoglutamic acid, 2β-sulfate

-   8. L-homoglutamic acid, 3α-sulfonic acid

-   9. L-homoglutamic acid, 3α-sulfate

-   10. L-homoglutamic acid, 3β-sulfonic acid

-   11. L-homoglutamic acid, 3β-sulfate

-   12. L-homoglutamic acid, 4α-sulfonic acid

-   13. L-homoglutamic acid, 4α-sulfate

-   14. L-homoglutamic acid, 4β-sulfonic acid

-   15. L-homoglutamic acid, 4β-sulfate

-   16. L-homoglutamic acid, 5α-sulfonic acid

-   17. L-homoglutamic acid, 5α-sulfate

-   18. L-homoglutamic acid, 5β-sulfonic acid

-   19. L-homoglutamic acid, 5β-sulfate

-   20. D-homoglutamic acid, N-sulfonic acid

-   21. Pentane-2β,5-dicarboxy-1-sulfonic acid

-   22. Pentane-2β,5-dicarboxy-1-sulfate

-   23. Butane-1β,4-dicarboxy-1-sulfonic acid

-   24. Butane-1β,4-dicarboxy-1-sulfate

-   25. D-homoglutamic acid, 2α-sulfonic acid

-   26. D-homoglutamic acid, 2α-sulfate

-   27. D-homoglutamic acid, 3α-sulfonic acid

-   28. D-homoglutamic acid, 3α-sulfate

-   29. D-homoglutamic acid, 3β-sulfonic acid

-   30. D-homoglutamic acid, 3β-sulfate

-   31. D-homoglutamic acid, 4α-sulfonic acid

-   32. D-homoglutamic acid, 4α-sulfate

-   33. D-homoglutamic acid, 4β-sulfonic acid

-   34. D-homoglutamic acid, 4β-sulfate

-   35. D-homoglutamic acid, 5α-sulfonic acid

-   36. D-homoglutamic acid, 5α-sulfate

-   37. D-homoglutamic acid, 5β-sulfonic acid

-   38. D-homoglutamic acid, 5β-sulfate

-   39. L-homoglutamine, N-sulfonic acid

-   40. Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid

-   41. Pentane-2α-carboxy, 5-carboxamido-1-sulfate

-   42. Butane-1α-carboxy, 4-carboxamido-1-sulfonic acid

-   43. Butane-1α-carboxy, 4-carboxamido-1-sulfate

-   44. L-homoglutamine, 2β-sulfonic acid

-   45. L-homoglutamine, 2β-sulfate

-   46. L-homoglutamine, 3α-sulfonic acid

-   47. L-homoglutamine, 3α-sulfate

-   48. L-homoglutamine, 3β-sulfonic acid

-   49. L-homoglutamine, 3β-sulfate

-   50. L-homoglutamine, 4α-sulfonic acid

-   51. L-homoglutamine, 4α-sulfate

-   52. L-homoglutamine, 4β-sulfonic acid

-   53. L-homoglutamine, 4β-sulfate

-   54. L-homoglutamine, 5α-sulfonic acid

-   55. L-homoglutamine, 5α-sulfate

-   56. L-homoglutamine, 5β-sulfonic acid

-   57. L-homoglutamine, 5β-sulfate

-   58. D-homoglutamine, N-sulfonic acid

-   59. Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid

-   60. Pentane-2β-carboxy, 5-carboxamido-1-sulfate

-   61. Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid

-   62. Butane-1β-carboxy, 4-carboxamido-1-sulfate

-   63. D-homoglutamine, 2α-sulfonic acid

-   64. D-homoglutamine, 2α-sulfate

-   65. D-homoglutamine, 3α-sulfonic acid

-   66. D-homoglutamine, 3α-sulfate

-   67. D-homoglutamine, 3β-sulfonic acid

-   68. D-homoglutamine, 3β-sulfate

-   69. D-homoglutamine, 4α-sulfonic acid

-   70. D-homoglutamine, 4α-sulfate

-   71. D-homoglutamine, 4β-sulfonic acid

-   72. D-homoglutamine, 4β-sulfate

-   73. D-homoglutamine, 5α-sulfonic acid

-   74. D-homoglutamine, 5α-sulfate

-   75. D-homoglutamine, 5β-sulfonic acid

-   76. D-homoglutamine, 5β-sulfate    The preferable specific compounds of the formulae (Ia), (Ib) and    (Ic) are the derivatives of aspartic acid, asparagine and    corresponding de-amino analogs (Table 1), glutamic acid, glutamine    and corresponding de-amino analogs (Table 2) and homoglutamic acid,    homoglutamine and corresponding de-amino analogs (Table 3) and non    toxic salts thereof and example compounds.

TABLE 1 Structure 1

1. L-Aspartic acid, N-Sulfonic acid Z = OH, R₁ = NHSO₃H, R₂ = R₃ = R₄ =H 2. L-Aspartic acid, 2β-sulfonic acid Z = OH, R₁ = NH₂, R₃ = R₄ = H, R₂= SO₃H 3. L-Aspartic acid, 2β-sulfate Z = OH, R₁ = NH₂, R₃ = R₄ = H, R₂= OSO₃H 4. L-aspartic acid, 3α-sulfonic acid Z = OH, R₁ = NH₂, R₂ = R₄ =H, R₃ = SO₃H 5. L-aspartic acid, 3α-sulfate Z = OH, R₁ = NH₂, R₂ = R₄ =H, R₃ = OSO₃H 6. L-aspartic acid, 3β-sulfonic acid Z = OH, R₁ = NH₂, R₂= R₃ = H, R₄ = SO₃H 7. L-aspartic acid, 3β-sulfate Z = OH, R₁ = NH₂, R₂= R₃ = H, R₄ = OSO₃H 8. 2α, 3-dicarboxy, propane-1-sulfonic acid Z = OH,R₁ = R₃ = R₄ = H, R₂ = CH₂SO₃H 9. 2α, 3-dicarboxy, propane-1-sulfate Z =OH, R₁ = R₃ = R₄ = H, R₂ = CH₂OSO₃H 10. 1α, 2-carboxy ethane sulfonicacid Z = OH, R₁ = R₃ = R₄ = H, R₂ = SO₃H 11. 1α, 2-carboxy ethanesulfate Z = OH, R₁ = R₃ = R₄ = H, R₂ = OSO₃H 12. D-aspartic acid,N-sulfonic acid Z = OH, R₂ = NHSO₃H, R₁ = R₃ = R₄ = H 13. 2β, 3-carboxy,propane-1-sulfonic acid Z = OH, R₂ = H, R₁ = CH₂SO₃H 14. 2β, 3-carboxy,propane-1-sulfate Z = OH, R₂ = H, R₁ = CH₂OSO₃H 15. 1β, 2-carboxyethane-1-sulfonic acid Z = OH, R₂ = H, R₁ = SO₃H 16. 1β, 2-carboxyethane-1-sulfate Z = OH, R₂ = H, R₁ = OSO₃H 17. D-aspartic acid,2α-sulfonic acid Z = OH, R₂ = NH₂, R₃ = R₄ = H, R₁ = SO₃H 18. D-asparticacid, 2α-sulfonic acid Z = OH, R₂ = NH₂, R₃ = R₄ = H, R₁ = SO₃H 19.D-Aspartic acid, 3α-sulfonic acid Z = OH, R₂ = NH₂, R₁ = R₄ = H, R₃ =SO₃H 20. D-Aspartic acid, 3α-sulfate Z = OH, R₂ = NH₂, R₁ = R₄ = H, R₃ =OSO₃H 21. D-Aspartic acid, 3β-sulfonic acid Z = OH, R₂ = NH₂, R₁ = R₃ =H, R₄ = SO₃H 22. D-aspartic acid, 3β-sulfate Z = OH, R₂ = NH₂, R₁ = R₃ =H, R₄ = OSO₃H 23. L-asparagine, N-sulfonic acid Z = NH₂, R₁ = NHSO₃H, R₂= R₃ = R₄ = H 24. 2α-carboxy, 3-carboxamido, propane-1-sulfonic acid Z =NH₂, R₁ = H, R₂ = CH₂SO₃H 25. 2α-carboxy, 3-carboxamido,propane-1-sulfate Z = NH₂, R₁ = H, R₂ = CH₂OSO₃H 26. 1α-carboxy,2-carboxamido, ethane sulfonic acid Z = NH₂, R₁ = H, R₂ = SO₃H 27.1α-carboxy, 2-carboxamido, ethane sulfate Z = NH₂, R₁ = H, R₂ = OSO₃H28. L-asparagine, 2β-sulfonic acid Z = R₁ = NH₂, R₂ = R₄ = H, R₂ = SO₃H29. L-asparagine, 2β-sulfate Z = R₁ = NH₂, R₂ = R₄ = H, R₃ = OSO₃H 30.L-asparagine, 3α-sulfonic acid Z = R₁ = NH₂, R₂ = R₄ = H, R₃ = SO₃H 31.L-asparagine, 3α-sulfate Z = R₁ = NH₂, R₂ = R₄ = H, R₃ = OSO₃H 32.L-asparagine, 3β-sulfonic acid Z = R₁ = NH₂, R₂ = R₃ = H, R₄ = SO₃H 33.L-asparagine, 3β-sulfate Z = R₁ = NH₂, R₂ = R₃ = H, R₄ = OSO₃H 34.D-asparagine, N-sulfonic acid Z = NH₂, R₂ = NHSO₃H, R₁ = R₃ = R₄ = H 35.2β-carboxy, 3-carboxamido, propane-1-sulfonic acid Z = NH₂, R₂ to R₄ =H, R₁ = CH₂SO₃H 36. 2β-carboxy, 3-carboxamido, propane-1-sulfate Z =NH₂, R₂ to R₄ = H, R₁ = CH₂SO₃H 37. 1β-carboxy, 2-carboxamido, ethanesulfonic acid] Z = OH, R₂ to R₄ = H, R₁ = SO₃H 38. 1β-carboxy,2-carboxamido, ethane sulfate Z = OH, R₂ to R₄ = H, R₁ = OSO₃H 39.D-asparagine, 2α-sulfonic acid Z = R₂ = NH₂, R₃ = R₄ = H, R₁ = SO₃H 40.D-asparagine, 2α-sulfate Z = R₂ = NH₂, R₃ = R₄ = H, R₁ = OSO₃H 41.D-asparagine, 3α-sulfonic acid Z = R₂ = NH₂, R₁ = R₄ = H, R₃ = SO₃H 42.D-asparagine, 3α-sulfate Z = R₂ = NH₂, R₁ = R₄ = H, R₃ = OSO₃H 43.D-asparagine, 3β-sulfonic acid Z = R₂ = NH₂, R₁ = R₃ = H, R₄ = SO₃H 44.D-asparagine, 3β-sulfate Z = R₂ = NH₂, R₁ = R₃ = H, R₄ = OSO₃H

TABLE 2 Structure 2

1. L-glutamic acid, N-sulfonic acid Z = OH, R₁ = NHSO₃H, R₂ = R₃ = R₄ =R₅ = R₆ = H 2. 2α, 4-dicarboxy, butane-1-sulfonic acid Z = OH, R₁, R₃ toR₆ = H, R₂ = CH₂SO₃H 3. 2α, 4-dicarboxy, butane-1-sulfate Z = OH, R₁, R₃to R₆ = H, R₂ = CH₂OSO₃H 4. 1α, 3-dicarboxy, propane sulfonic acid Z =OH, R₁, R₃ to R₆ = H, R₂ = SO₃H 5. 1α, 3-dicarboxy, propane sulfate Z =OH, R₁, R₃ to R₆ = H, R₂ = OSO₃H 6. 1β, 3-dicarboxy, propane sulfate Z =OH, R₂ to R₆ = H, R₁ = OSO₃H 7. 1β, 3-dicarboxy, propane sulfonic acid Z= OH, R₂ to R₆ = H, R₁ = SO₃H 8. L-glutamic acid, 2β-sulfonic acid Z =OH, R₁ = NH₂, R₃ to R₆ = H, R₂ = SO₃H 9. L-glutamic acid, 2β-sulfate Z =OH, R₁ = NH₂, R₃ to R₆ = H, R₂ = OSO₃H 10. L-glutamic acid, 3α-sulfonicacid Z = OH, R₁ = NH₂, R₂ = H, R₄ to R₆ = H, R₃ = SO₃H 11. L-glutamicacid, 3α-sulfate Z = OH, R₁ = NH₂, R₂ = H, R₄ to R₆ = H, R₃ = OSO₃H 12.L-glutamic acid, 3β-sulfonic acid Z = OH, R₁ = NH₂, R₂ = R₃ = R₅ = R₆ =H, R₄ = SO₃H 13. L-glutamic acid, 3β-sulfate Z = OH, R₁ = NH₂, R₂ = R₃ =R₅ = R₆ = H, R₄ = OSO₃H 14. L-glutamic acid, 4α-sulfonic acid Z = OH, R₁= NH₂, R₂ = R₃ = R₄ = R₆ = H, R₅ = SO₃H 15. L-glutamic acid, 4α-sulfateZ = OH, R₁ = NH₂, R₂ = R₃ = R₄ = R₆ = H, R₅ = OSO₃H 16. L-glutamic acid,4β-sulfonic acid Z = OH, R₁ = NH₂, R₂ to R₅ = H, R₆ = SO₃H 17.L-glutamic acid, 4β-sulfate Z = OH, R₁ = NH₂, R₂ to R₅ = H, R₆ = OSO₃H18. D-glutamic acid, N-sulfonic acid Z = OH, R₂ = NHSO₃H, R₁, R₃ to R₆ =H 19. 2β, 4-dicarboxy, butane-1-sulfonic acid Z = OH, R₂ to R₆ = H, R₁ =CH₂SO₃H 20. 2β, 4-dicarboxy, butane-1-sulfate Z = OH, R₂ to R₆ = H, R₁ =CH₂OSO₃H 21. D-glutamic acid, 2α-sulfonic acid Z = OH, R₂ = NH₂, R₃ toR₆ H, R₁ = SO₃H 22. D-glutamic acid, 2α-sulfate Z = OH, R₂ = NH₂, R₃ toR₆ H, R₁ = OSO₃H 23. D-glutamic acid, 3α-sulfonic acid Z = OH, R₂ = NH₂,R₁, R₄ to R₆ H, R₃ = SO₃H 24. D-glutamic acid, 3α-sulfate Z = OH, R₂ =NH₂, R₁, R₄ to R₆ H, R₃ = OSO₃H 25. D-glutamic acid, 3β-sulfonic acid Z= OH, R₂ = NH₂, R₁ = R₃ = R₅ = R₆ = H, R₄ = SO₃H 26. D-glutamic acid,3β-sulfate Z = OH, R₂ = NH₂, R₁ = R₃ = R₅ = R₆ = H, R₄ = OSO₃H 27.D-glutamic acid, 4α-sulfonic acid Z = OH, R₂ = NH₂, R₁ = R₃ = R₄ = R₆ =H, R₅ = SO₃H 28. D-glutamic acid, 4α-sulfate Z = OH, R₂ = NH₂, R₁ = R₃ =R₄ = R₆ = H, R₅ = OSO₃H 29. D-glutamic acid, 4β-sulfonic acid Z = OH, R₂= NH₂, R₁ = R₃ = R₄ = R₅ = H, R₆ = SO₃H 30. D-glutamic acid, 4β-sulfateZ = OH, R₂ = NH₂, R₁ = R₃ = R₄ = R₅ = H, R₆ = OSO₃H 31. L-glutamine,N-sulfonic acid Z = NH₂, R₁ = NHSO₃H, R₂ to R₆ = H 32. L-glutamine,2β-sulfonic acid Z = R₁ = NH₂, R₃ to R₆ = H, R₂ = SO₃H 33. L-glutamine,2β-sulfate Z = R₁ = NH₂, R₃ to R₆ = H, R₂ = OSO₃H 34. L-glutamine,3α-sulfonic acid Z = R₁ = NH₂, R₂ = H, R₃ to R₆ = H, R₃ = SO₃H 35.L-glutamine, 3α-sulfate Z = R₁ = NH₂, R₂ = H, R₃ to R₆ = H, R₃ = OSO₃H36. L-glutamine, 3β-sulfonic acid Z = R₁ = NH₂, R₂ = R₃ = R₅ = R₆ = H,R₄ = SO₃H 37. L-glutamine, 3β-sulfate Z = R₁ = NH₂, R₂ = R₃ = R₅ = R₆ =H, R₄ = OSO₃H 38. L-glutamine, 4α-sulfonic acid Z = R₁ = NH₂, R₂ = R₃ =R₄ = R₆ = H, R₅ = SO₃H 39. L-glutamine, 4α-sulfate Z = R₁ = NH₂, R₂ = R₃= R₄ = R₆ = H, R₅ = OSO₃H 40. L-glutamine, 4β-sulfonic acid Z = R₁ =NH₂, R₂ to R₅ = H, R₆ = SO₃H 41. L-glutamine, 4β-sulfate Z = R₁ = NH₂,R₂ to R₅ = H, R₆ = OSO₃H 42. 2α-carboxy, 4-carboxamido,butane-1-sulfonic acid Z = NH₂, R₁, R₃ to R₆ = H, R₂ = CH₂SO₃H 43.2α-carboxy, 4-carboxamido, butane-1-sulfate Z = NH₂, R₁, R₃ to R₆ = H,R₂ = CH₂OSO₃H 44. 1α-carboxy, 3-carboxamido, propane-1-sulfonic acid Z =NH₂, R₁, R₃ to R₆ = H, R₂ = SO₃H 45. 1α-carboxy, 3-carboxamido,propane-1-sulfate Z = NH₂, R₁, R₃ to R₆ = H, R₂ = OSO₃H 46. 1β-carboxy,3-carboxamido, propane-1-sulfate Z = NH₂, R₂ to R₆ = H, R₁ = OSO₃H 47.1β-carboxy, 3-carboxamido, propane-1-sulfonic acid Z = NH₂, R₂ to R₆ =H, R₁ = SO₃H 48. D-glutamine, N-sulfonic acid Z = NH₂, R₂ = NHSO₃H; R₁ =H, R₃ to R₆ = H 49. 2β-carboxy, 4-carboxamido, butane-1-sulfonic acid Z= NH₂, R₂ to R₆ = H, R₁ = CH₂SO₃H 50. 2β-carboxy, 4-carboxamido,butane-1-sulfate Z = NH₂, R₂ to R₆ = H, R₁ = CH₂OSO₃H 51. D-glutamine,2α-sulfonic acid Z = NH₂, R₂ = NH₂, R₃ to R₆ = H, R₁ = SO₃H 52.D-glutamine, 2α-sulfate Z = NH₂, R₂ = NH₂, R₃ to R₆ = H, R₁ = OSO₃H 53.D-glutamine, 3α-sulfonic acid Z = NH₂, R₂ = NH₂, R₁, R₄ to R₆ H, R₃ =SO₃H 54. D-glutamine, 3α-sulfate Z = R₂ = NH₂, R₁, R₄ to R₆ H, R₃ =OSO₃H 55. D-glutamine, 3β-sulfonic acid Z = R₂ = NH₂, R₁ = R₃ = R₅ = R₆= H, R₄ = SO₃H 56. D-glutamine, 3β-sulfate Z = R₂ = NH₂, R₁ = R₃ = R₅ =R₆ = H, R₄ = OSO₃H 57. D-glutamine, 4α-sulfonic acid Z = R₂ = NH₂, R₁ =R₃ = R₄ = R₆ = H, R₅ = SO₃H 58. D-glutamine, 4α-sulfate Z = R₂ = NH₂, R₁= R₃ = R₄ = R₆ = H, R₅ = OSO₃H 59. D-glutamine, 4β-sulfonic acid Z = R₂= NH₂, R₁ = R₃ = R₄ = R₅ = H, R₆ = SO₃H 60. D-glutamine, 4β-sulfate Z =R₂ = NH₂, R₁ = R₃ = R₄ = R₅ = H, R₆ = OSO₃H

TABLE 3 structure 3

1. L-homoglutamic acid, N-sulfonic acid Z = OH, R₁ = NHSO₃H, R₂ to R₈ =H 2. Pentane-2α, 5-dicarboxy-1-sulfonic acid Z = OH, R₁, R₃ to R₈ = H,R₂ = CH₂SO₃H 3. Pentane-2α, 5-dicarboxy-1-sulfate Z = OH, R₁, R₃ to R₈ =H, R₂ = CH₂OSO₃H 4. Butane-1α, 4-dicarboxy-1-sulfonic acid Z = OH, R₁,R₃ to R₈ = H, R₂ = SO₃H 5. Butane-1α, 4-dicarboxy-1-sulfate Z = OH, R₁,R₃ to R₈ = H, R₂ = OSO₃H 6. L-homoglutamic acid, 2β-sulfonic acid Z =OH, R₁ = NH₂, R₃ to R₈ = H, R₂ = SO₃H 7. L-homoglutamic acid, 2β-sulfateZ = OH, R₁ = NH₂, R₃ to R₈ = H, R₂ = OSO₃H 8. L-homoglutamic acid,3α-sulfonic acid Z = OH, R₁ = NH₂, R₂ = H, R₄ to R₈ H, R₃ = SO₃H 9.L-homoglutamic acid, 3α-sulfate Z = OH, R₁ = NH₂, R₂ = H, R₄ to R₈ H, R₃= OSO₃H 10. L-homoglutamic acid, 3β-sulfonic acid Z = OH, R₁ = NH₂, R₂ =R₃ = H, R₅ to R₈ = H, R₄ = SO₃H 11. L-homoglutamic acid, 3β-sulfate Z =OH, R₁ = NH₂, R₂ = R₃ = H, R₅ to R₈ = H, R₄ = OSO₃H 12. L-homoglutamicacid, 4α-sulfonic acid Z = OH, R₁ = NH₂, R₂ = R₃ = R₄ = H, R₆ to R₈ = H,R₅ = SO₃H 13. L-homoglutamic acid, 4α-sulfate Z = OH, R₁ = NH₂, R₂ = R₃= R₄ = H, R₆ to R₈ = H, R₅ = OSO₃H 14. L-homoglutamic acid, 4β-sulfonicacid Z = OH, R₁ = NH₂, R₂ = R₅ = H, R₇ = R₈ = H, R₆ = SO₃H 15.L-homoglutamic acid, 4β-sulfate Z = OH, R₁ = NH₂, R₂ = R₅ = H, R₇ = R₈ =H, R₆ = OSO₃H 16. L-homoglutamic acid, 5α-sulfonic acid Z = OH, R₁ =NH₂, R₂ to R₆ = H, R₈ = H, R₇ = SO₃H 17. L-homoglutamic acid, 5α-sulfateZ = OH, R₁ = NH₂, R₂ to R₆ = H, R₈ = H, R₇ = OSO₃H 18. L-homoglutamicacid, 5β-sulfonic acid Z = OH, R₁ = NH₂, R₂ to R₇ = H, R₈ = SO₃H 19.L-homoglutamic acid, 5β-sulfate Z = OH, R₁ = NH₂, R₂ to R₇ = H, R₈ =OSO₃H 20. D-homoglutamic acid, N-sulfonic acid Z = OH, R₂ = NHSO₃H, R₁,R₃ to R₈ = H 21. Pentane-2β, 5-dicarboxy-1-sulfonic acid Z = OH, R₂ toR₈ = H, R₁ = CH₂SO₃H 22. Pentane-2β, 5-dicarboxy-1-sulfate Z= OH, R₂ toR₈ = H, R₁ = CH₂OSO₃H 23. Butane-1β, 4-dicarboxy-1-sulfonic acid Z = OH,R₂ to R₈ = H, R₁ = SO₃H 24. Butane-1β, 4-dicarboxy-1-sulfate Z = OH, R₂to R₈ = H, R₁ = OSO₃H 25. D-homoglutamic acid, 2α-sulfonic acid Z = OH,R₂ = NH₂, R₃ to R₈ = H, R₁ = SO₃H 26. D-homoglutamic acid, 2α-sulfate Z= OH, R₂ = NH₂, R₃ to R₈ = H, R₁ = OSO₃H 27. D-homoglutamic acid,3α-sulfonic acid Z = OH, R₂ = NH₂, R₁, R₄ to R₈ H, R₃ = SO₃H 28.D-homoglutamic acid, 3α-sulfate Z = OH, R₂ = NH₂, R₁, R₄ to R₈ H, R₃ =OSO₃H 29. D-homoglutamic acid, 3β-sulfonic acid Z = OH, R₂ = NH₂, R₁ =R₃ = H, R₅ to R₈ = H, R₄ = SO₃H 30. D-homoglutamic acid, 3β-sulfate Z =OH, R₂ = NH₂, R₁ = R₃ = H, R₅ to R₈ = H, R₄ = OSO₃H 31. D-homoglutamicacid, 4α-sulfonic acid Z = OH, R₂ = NH₂, R₁ = R₃ = R₄ = H, R₆ to R₈ = H,R₅ = SO₃H 32. D-homoglutamic acid, 4α-sulfate Z = OH, R₂ = NH₂, R₁ = R₃= R₄ = H, R₆ to R₈ = H, R₅ = OSO₃H 33. D-homoglutamic acid, 4β-sulfonicacid Z = OH, R₂ = NH₂, R₁ = H, R₃ to R₅ = H, R₇ = R₈ = H, R₆ = SO₃H 34.D-homoglutamic acid, 4β-sulfate Z = OH, R₂ = NH₂, R₁ = H, R₃ to R₅ = H,R₇ = R₈ = H, R₆ = OSO₃H 35. D-homoglutamic acid, 5α-sulfonic acid Z =OH, R₂ = NH₂, R₁ = R₈ = H, R₃ to R₆ = H, R₇ = SO₃H 36. D-homoglutamicacid, 5α-sulfate Z = OH, R₂ = NH₂, R₁ = R₈ = H, R₃ to R₆ = H, R₇ = OSO₃H37. D-homoglutamic acid, 5β-sulfonic acid Z = OH, R₂ = NH₂, R₁ = H, R₃to R₇ = H, R₈ = SO₃H 38. D-homoglutamic acid, 5β-sulfate Z = OH, R₂ =NH₂, R₁ = H, R₃ to R₇ = H, R₈ = OSO₃H 39. L-homoglutamine, N-sulfonicacid Z = NH₂, R₁ = NHSO₃H, R₂ to R₈ = H 40. Pentane-2α-carboxy,5-carboxamido-1-sulfonic acid Z = NH₂, R₁ and R₃ to R₈ = H, R₂ = CH₂SO₃H41. Pentane-2α-carboxy, 5-carboxamido-1-sulfate Z = NH₂, R₁ and R₃ to R₈= H, R₂ = CH₂OSO₃H 42. Butane-1α-carboxy, 4-carboxamido-1-sulfonic acidZ = NH₂, R₁ and R₃ to R₈ = H, R₂ = SO₃H 43. Butane-1α-carboxy,4-carboxamido-1-sulfate Z = NH₂, R₁ and R₃ to R₈ = H, R₂ = OSO₃H 44.L-homoglutamine, 2β-sulfonic acid Z = R₁ = NH₂, R₃ to R₈ = H, R₂ = SO₃H45. L-homoglutamine, 2β-sulfate Z = R₁ = NH₂, R₃ to R₈ = H, R₂ = OSO₃H46. L-homoglutamine, 3α-sulfonic acid Z = R₁ = NH₂, R₂ = H, R₄ to R₈ =H, R₃ = SO₃H 47. L-homoglutamine, 3α-sulfate Z = R₁ = NH₂, R₂ = H, R₄ toR₈ = H, R₃ = OSO₃H 48. L-homoglutamine, 3β-sulfonic acid Z = R₁ = NH₂,R₂ = R₃ = H, R₅ to R₈ = H, R₄ = SO₃H 49. L-homoglutamine, 3β-sulfate Z =R₁ = NH₂, R₂ = R₃ = H, R₅ to R₈ = H, R₄ = OSO₃H 50. L-homoglutamine,4α-sulfonic acid Z = R₁ = NH₂, R₂ = R₃ = R₄ = H, R₆ to R₈ = H, R₅ = SO₃H51. L-homoglutamine, 4α-sulfate Z = R₁ = NH₂, R₂ = R₃ = R₄ = H, R₆ to R₈= H, R₅ = OSO₃H 52. L-homoglutamine, 4β-sulfonic acid Z = R₁ = NH₂, R₂ =R₅ = H, R₇ = R₈ = H, R₆ = SO₃H 53. L-homoglutamine, 4β-sulfate Z = R₁ =NH₂, R₂ = R₅ = H, R₇ = R₈ = H, R₆ = OSO₃H 54. L-homoglutamine,5α-sulfonic acid Z = R₁ = NH₂, R₂ to R₆ = H, R₈ = H, R₇ = SO₃H 55.L-homoglutamine, 5α-sulfate Z = R₁ = NH₂, R₂ to R₆ = H, R₈ = H, R₇ =OSO₃H 56. L-homoglutamine, 5β-sulfonic acid Z = R₁ = NH₂, R₂ to R₇ = H,R₈ = SO₃H 57. L-homoglutamine, 5β-sulfate Z = R₁ = NH₂, R₂ to R₇ = H, R₈= OSO₃H 58. D-homoglutamine, N-sulfonic acid Z = NH₂, R₂ = NHSO₃H, R₁and R₃ to R₈ = H 59. Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid Z= NH₂, R₂ to R₈ = H, R₁ = CH₂SO₃H 60. Pentane-2β-carboxy,5-carboxamido-1-sulfate Z = NH₂, R₂ to R₈ = H, R₁ = CH₂OSO₃H 61.Butane-1β-carboxy, 4-carboxamido-1-sulfonic acid Z = NH₂, R₂ to R₈ = H,R₁ = SO₃H 62. Butane-1β-carboxy, 4-carboxamido-1-sulfate Z = NH₂, R₂ toR₈ = H, R₁ = OSO₃H 63. D-homoglutamine, 2α-sulfonic acid Z = R₂ = NH₂,R₃ to R₈ H, R₁ = SO₃H 64. D-homoglutamine, 2α-sulfate Z = R₂ = NH₂, R₃to R₈ H, R₁ = OSO₃H 65. D-homoglutamine, 3α-sulfonic acid Z = R₂ = NH₂,R₁, R₄ to R₈ H, R₃ = SO₃H 66. D-homoglutamine, 3α-sulfate Z = R₂ = NH₂,R₁, R₄ to R₈ H, R₃ = OSO₃H 67. D-homoglutamine, 3β-sulfonic acid Z = R₂= NH₂, R₁ = R₃ = H, R₅ to R₈ = H, R₄ = SO₃H 68. D-homoglutamine,3β-sulfate Z = R₂ = NH₂, R₁ = R₃ = H, R₅ to R₈ = H, R₄ = OSO₃H 69.D-homoglutamine, 4α-sulfonic acid Z = R₂ = NH₂, R₁ = R₃ = R₄ = H, R₆ toR₈ = H, R₅ = SO₃H 70. D-homoglutamine, 4α-sulfate Z = R₂ = NH₂, R₁ = R₃= R₄ = H, R₆ to R₈ = H, R₅ = OSO₃H 71. D-homoglutamine, 4β-sulfonic acidZ = R₂ = NH₂, R₁ = H, R₃ to R₅ = H, R₇ = R₈ = H, R₆ = SO₃H 72.D-homoglutamine, 4β-sulfate Z = R₂ = NH₂, R₁ = H, R₃ to R₅ = H, R₇ = R₈= H, R₆ = OSO₃H 73. D-homoglutamine, 5α-sulfonic acid Z = R₂ = NH₂, R₁ =R₈ = H, R₃ to R₆ = H, R₇ = SO₃H 74. D-homoglutamine, 5α-sulfate Z = R₂ =NH₂, R₁ = R₈ = H, R₃ to R₆ = H, R₇ = OSO₃H 75. D-homoglutamine,5β-sulfonic acid Z = R₂ = NH₂, R₁ = H, R₃ to R₇ = H, R₈ = SO₃H 76.D-homoglutamine, 5β-sulfate Z = R₂ = NH₂, R₁ = H, R₃ to R₇ = H, R₈ =OSO₃H

REFERENCE EXAMPLE

The following reference example and examples illustrate the presentinvention but do not limit the present invention.

The solvents in the parenthesis show the developing and eluting solventsand the ratios of the solvent used are by volume in the chromatographicseparation or TLC.

The solvents in the parenthesis in NMR show the solvents used inmeasurement.

REFERENCE EXAMPLE AND EXAMPLE

The following reference example and examples illustrate the presentinvention but do not limit the present invention. The solvents in theparenthesis show the developing and eluting solvents and the ratios ofthe solvent used are by volume in the chromatographic separation or TLC.The solvents in the parenthesis in NMR show the solvents used inmeasurement.

Reference Example 1

L-glutamyl, N-sulfonic Acid from Glutamic Acid Mono Tertiary Butyl Ester

Glutamic acid monotertiary butyl ester (1 eq.) was added portion-wise toa solution of SO₂Cl₂ (2 eq.) in dry CH₂Cl₂ at 0° C. followed by Et₃N (3eq.). Resulting solution stirred for 8 hrs at r. t. when TLC showedcomplete consumption of starting material. Solvent was evaporated andthe crude was dried in vacuum. 3 ml water was added to it and the slurrywas stirred for 1 hr. To the slurry was added 45 ml CH₂Cl₂ followed by 3eq of TFA at 0° C. The resulting solution was stirred at r. t. for 24hrs. The solvent was evaporated and dried in vacuum. The pseudomolecular ion, [M−H]⁻ at 226.0049 confirmed the structure of the productL-glutamyl, N-sulfonic acid (calculated for C5H8NO7S; 226.0026).

Reference Example 2

L-glutamyl, N-sulfonic Acid from Glutamic Acid Di Tertiary Butyl Ester

Glutamic acid ditertiary butyl ester (1 eq.) was added portion-wise to asolution of SO₂Cl₂ (2 eq.) in dry CH₂Cl₂ at 0° C. followed by Et₃N (3eq.). Resulting solution stirred for 8 hrs at r. t. when TLC showedcomplete consumption of starting material. Solvent was evaporated andthe crude was dried in vacuum. 3 ml water was added to it and the slurrywas stirred for 1 hr. To the slurry was added 45 ml CH₂Cl₂ followed by 3eq of TFA at 0° C. The resulting solution was stirred at r. t. for 24hrs. The solvent was evaporated and dried in vacuum. The pseudomolecular ion, [M−H]⁻ at 226.0049 confirmed the structure of the productL-glutamyl, N-sulfonic acid (calculated for C₅H₈NO7S; 226.0026).

Reference Example 3

L-aspartyl, N-sulfonic Acid from L-aspartic Acid Di Tertiary Butyl Ester

L-aspartic acid di tertiary butyl ester (1 eq.) was added portion-wiseto a solution of SO₂Cl₂ (2 eq.) in dry CH₂Cl₂ at 0° C. followed by Et₃N(3 eq.). Resulting solution stirred for 8 hrs at r. t. when TLC showedcomplete consumption of starting material. Solvent was evaporated andthe crude was dried in vacuum. 3 ml water was added to it and the slurrywas stirred for 1 hr. To the slurry was added 45 ml CH₂Cl₂ followed by 3eq of TFA at 0° C. The resulting solution was stirred at r. t. for 24hrs. The solvent was evaporated and dried in vacuum. The pseudomolecular ion, [M−H]⁻ at 211.9885 confirmed the structure of the productL-aspartyl, N-sulfonic acid (calculated for C4H6NO7S; 211.9870).

Reference Example 4

L-homoglutamyl, N-sulfonic Acid from L-homoglutamic Acid Di TertiaryButyl Ester

L-Homoglutamic acid di tertiary butyl ester (1 eq.) was addedportion-wise to a solution of SO₂Cl₂ (2 eq.) in dry CH₂Cl₂ at 0° C.followed by Et₃N (3 eq.). Resulting solution stirred for 8 hrs at r. t.when TLC showed complete consumption of starting material. Solvent wasevaporated and the crude was dried in vacuum. 3 ml water was added to itand the slurry was stirred for 1 hr. To the slurry was added 45 mlCH₂Cl₂ followed by 3 eq of TFA at 0° C. The resulting solution wasstirred at r. t. for 24 hrs. The solvent was evaporated and dried invacuum. The pseudo molecular ion, [M−H]⁻ at 240.0169 confirmed thestructure of the product L-Homoglutamyl, N-sulfonic acid (calculated forC6H10NO7S; 240.0182).

Reference Example 5

The calcium salt of L-glutamyl-N-sulphonic acid was prepared by adding 1M equivalent of CaCl₂ solution and incubated at temperature ranging from30±5° C. The resulting complex was freeze-dried. The freeze-driedcompound was reconstituted in sterilized distilled water and assessed ina dose-dependent manner for inhibition of osteoclast differentiation(Table A).

TABLE A Effect of compound 1 (L-glutamyl-N-sulphonic acid, Ca salt) onosteoclast formation Number of TRAP-positive multinuclear cells/wellCulture of 96 well plate conditions (Mean ± SEM) % inhibition M-CSF 0 —M-CSF + RANKL 138.00 ± 9.37  — M-CSF + RANKL + 109.67 ± 9.79  21.01compound 1 (0.5 μg/ml) M-CSF + RANKL + 52.17 ± 6.42  62.19 compound 1(1.5 μg/ml) M-CSF + RANKL + 14.67 ± 1.98  89.36 compound 1 (3.0 μg/ml)M-CSF + RANKL + 2.83 ± 1.05 97.94 compound 1 (5.0 μg/ml)

-   -   Culture of murine bone marrow cells in the presence of M-CSF and        RANKL induces the formation of osteoclasts, which were detected        as TRAP-positive cells. A dose dependent inhibition in the        number of osteoclast cells generated as observed with increasing        dose of compound 1. Values given are the mean±SD of five        separate experiments

Reference Example 6

The calcium salt of L-glutamic acid was prepared by adding 1 Mequivalent of CaCl₂ solution and incubated at temperature ranging from30±5° C. The resulting complex was freeze-dried. The freeze-driedcompound was reconstituted in sterilized distilled water and assessed ina dose-dependent manner for inhibition of osteoclast differentiation(Table B).

TABLE B Effect of L-glutamic acid, calcium salt on osteoclast formationNumber of TRAP-positive multinuclear cells/well of 96 well Culture plateconditions (Mean ± SEM) % inhibition M-CSF 0 — M-CSF + RANKL 158.33 ±12.00 — M-CSF + RANKL + 167.17 ± 7.95  0 compound 2 (0.5 μg/ml) M-CSF +RANKL + 152.83 ± 10.47 3.47 compound 2 (1.5 μg/ml) M-CSF + RANKL +130.50 ± 13.57 17.37 compound 2 (3.0 μg/ml) M-CSF + RANKL + 119.50 ±10.00 24.52 compound 2 (5.0 μg/ml) For detail see legend to example 5

Reference Example 7

The L-glutamyl-N-sulphonic acid prepared as described in Examples 1 & 2was reconstituted in sterilized distilled water and assessed in adose-dependent manner for inhibition of osteoclast differentiation(Table D).

TABLE-D Effect of L-glutamyl-N-sulphonic acid on osteoclast formationNumber of TRAP-positive multinuclear cells/well of 96 well Culture plateconditions (Mean ± SEM) % inhibition M-CSF 0 — M-CSF + RANKL  146.83 ±11.89 — M-CSF + RANKL + 154.67 ± 8.43 0 compound 3 (0.5 μg/ml) M-CSF +RANKL + 150.33 ± 8.82 0 compound 3 (1.5 μg/ml) M-CSF + RANKL + 112.67 ±8.63 23.23 compound 3 (3.0 μg/ml) M-CSF + RANKL + 110.00 ± 6.72 25.08compound 3 (5.0 μg/ml) For detail see legend to example 5

Reference Example 8

The L-glutamic acid was reconstituted in sterilized distilled water andassessed in a dose-dependent manner for inhibition of osteoclastdifferentiation (Table E).

TABLE E Effect of L-glutamic acid on osteoclast formation Number ofTRAP-positive multinuclear cells/well of 96 well Culture plateconditions (Mean ± SEM) % inhibition M-CSF 0 — M-CSF + RANKL 156.00 ±12.26 0 M-CSF + RANKL + 173.33 ± 6.50  0 compound 4 (0.5 μg/ml) M-CSF +RANKL + 155.00 ± 8.23  0.64 compound 4 (1.5 μg/ml) M-CSF + RANKL +145.83 ± 14.71 7.05 compound 4 (3.0 μg/ml) M-CSF + RANKL + 112.67 ±10.74 27.77 compound 4 (5.0 μg/ml) For detail see legend to example 5

Reference Example 9

The L-Aspartic acid, N-sulphonic acid as prepared in example 3 was mixedwith 1 M equivalent of CaCl₂ solution and incubated at temperatureranging from 30±5° C. The resulting complex was freeze-dried. Thefreeze-dried compound was reconstituted in sterilized distilled waterand assessed in a dose-dependent manner for inhibition of osteoclastdifferentiation (Table F).

TABLE F Effect of L-Aspartic acid, N-sulphonic acid calcium salt onosteoclast formation Number of TRAP-positive multinuclear cells/well of96 well Culture plate conditions (Mean ± SEM) % inhibition M-CSF 0 —M-CSF + RANKL 158.33 ± 11.26 0 M-CSF + RANKL + 127.30 ± 5.50  19.70compound 4 (0.5 μg/ml) M-CSF + RANKL + 86.23 ± 7.23 45.16 compound 4(1.5 μg/ml) M-CSF + RANKL + 44.50 ± 4.80 71.90 compound 4 (3.0 μg/ml)M-CSF + RANKL + 26.67 ± 0.73 83.26 compound 4 (5.0 μg/ml) For detail seelegend to example 5Reference Example 10

L-homoglutamic acid, N-sulphonic acid as prepared in example 4 was mixedwith 1 M equivalent of CaCl₂ solution and incubated at temperatureranging from 30±5° C. The resulting complex was freeze-dried. Thefreeze-dried compound was reconstituted in sterilized distilled waterand assessed in a dose-dependent manner for inhibition of osteoclastdifferentiation (Table G).

TABLE G Effect of L-homoglutamic acid, N-sulphonic acid, calcium salt onosteoclast formation Number of TRAP-positive multinuclear cells/well of96 well Culture plate conditions (Mean ± SEM) % inhibition M-CSF 0 —M-CSF + RANKL 146..83 ± 12.00  — M-CSF + RANKL + 138.57 ± 7.95  5.55compound 2 (0.5 μg/ml) M-CSF + RANKL + 106.23 ± 10.47 27.60 compound 2(1.5 μg/ml) M-CSF + RANKL +  78.57 ± 13.57 46.40 compound 2 (3.0 μg/ml)M-CSF + RANKL +  46.22 ± 10.00 68.50 compound 2 (5.0 μg/ml) For detailsee legend to example 5

Reference Example 11

A. In Vitro Osteoclastogenesis Assay

For in vitro osteoclastogenesis bone marrow cells were isolated from5-to 8-wk-old Balb/c mice. Mice were sacrificed by cervical dislocationand femora and tibiae were aseptically removed and dissected free ofadherent soft tissues. The bone ends were cut, and the marrow cavity wasflushed out with medium MEM from one end of the bone using a sterile21-gauge needle. The bone marrow suspension was carefully agitated witha plastic Pasteur pipette to obtain a single-cell suspension. The cellswere washed twice and resuspended (10⁶ cells/ml) in αMEM containing 10%FBS. Stromal cell-free, M-CSF-dependent, osteoclast precursor cells wereprepared from these cells as previously described (Wani et al. 1999).Briefly, bone marrow cells were incubated for 24 h in αMEM containing10% FBS in the presence of M-CSF (10 ng/ml) at a density of 3×10⁵cells/ml in a 75 cm² flask. After 24 h, nonadherent cells were harvestedand layered on a Ficoll-Hypaque gradient. Cells at the gradientinterface were collected, washed and resuspended (5×10⁵/ml) in αMEMcontaining 10% FBS. In this study, we called these stromal cell-free,M-CSF-dependent, nonadherent cells as osteoclast precursors. Theseosteoclast precursors were added to 96-well plates (100 μl/well)containing plastic coverslips. Each well received further 100 μl ofmedium containing M-CSF (30 ng/ml), RANKL (30 ng/ml) without or withvarious concentrations of purified compound. Cultures were fed every 2-3days and after incubation for 6 days osteoclast formation was evaluatedby tartrate-resistant acid phosphatase (TRAP) staining. The number ofTRAP-positive multinucleated cells (MNCs) containing 3 or more nucleiwas scored.

B. Characterization of Osteoclasts by TRAP Staining

Osteoclast formation was evaluated by quantification of TRAP-positiveMNCs as described previously (Khapli et al. 2003). TRAP ispreferentially expressed at high levels in osteoclast and is considered,especially in the mouse, to be an osteoclast marker. Cytochemicalstaining for TRAP is widely used for identifying the osteoclasts in vivoand in vitro. It is claimed to be specific for osteoclasts in bone.After incubation, cells on cover slips were washed in PBS, fixed in 10%formalin for 10 min and stained for acid phosphatase in the presence of0.05 M sodium tartrate. The substrate used was napthol AS-BI phosphate.Only those cells that were strongly TRAP-positive (dark red) counted bylight microscopy.

C. In Vitro Bone Resorption Assay

Osteoclast has the ability to excavate authentic resorption lacunae invivo and in vitro. Bone resorption is the unique function of theosteoclast and is therefore the most useful means of distinguishing itfrom other cell types. M-CSF-dependent, non-adherent bone marrow cellswere incubated for 10 days on bovine cortical bone slices in thepresence of M-CSF, RANKL with or without various concentrations ofcompounds. Bone slices were examined for resorption pits by reflectedlight microscopy as previously described (Wani et al. 1999).

BRIEF DESCRIPTION OF THE FIGURES

The patent application file contains at least one drawing executed incolor. Copies of this patent application publication with color drawingswill be provided by the Office upon request and payment of the necessaryfee.

FIG. 1: Illustration of Plate 1: Effect of compound as given in example3 on RANKL-induced osteoclast differentiation from haemopoieticprecursors of monocytes/macrophage lineage. Mice osteoclast precursorswere incubated in the presence of M-CSF and RANKL in the absence andpresence of the compound. Photomicrographs showing TRAP-positiveosteoclasts in the absence (Plate 1A) and presence (Plate 1B) of thecompound. This compound significantly inhibited osteoclast formation.

FIG. 2: Illustration of Plate 2: Effect of compound as described inexample 4 on RANKL-induced osteoclast differentiation from haemopoieticprecursors of monocytes/macrophage lineage. Photomicrographs showingTRAP-positive osteoclasts induced by M-CSF and RANKL in the absence(Plate 2A) and presence (Plate 2B) of the compound. This compound showedno inhibitory effect on osteoclast differentiation.

1. A method for inhibiting osteoclast formation in a subject in needthereof, comprising the step of administering a pharmaceuticallyeffective amount of an isolated compound of the general formulaZOC—(CRR)_(m)—COOH, wherein: m=2, 3 or 4; Z is OH or NH₂; one R in thecompound is from the group consisting of SO₃H, OSO₃H, CH₂—SO₃H,CH₂—OSO₃H, and NHSO₃H, and the remaining Rs are H or NH₂, optionallywith an additive, excipient, diluent or carrier.
 2. The method accordingto claim 1, for inhibiting formation of mononuclear TRAP-positiveosteoclasts.
 3. The method according to claim 1, for inhibitingformation of multinuclear TRAP-positive osteoclasts.
 4. The methodaccording to claim 1, wherein the pharmaceutically effective amount is 5to 10 mg/kg of body weight.
 5. The method according to claim 1,comprising administering the compound for between 5 and 30 days.
 6. Themethod according to claim 1, comprising administering the compound forat least 30 days.
 7. The method according to claim 1, comprisingadministering the compound for at least 60 days.
 8. The method accordingto claim 1, comprising administering the compound for at least 90 days.9. The method according to claim 1, wherein the compound has thestructure shown below and the formula ZOC—CR₃R₄—CR₁R₂—COOH, wherein oneof R₁ to R₄ is selected from the group consisting of SO₃H, OSO₃H,CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining are H or NH₂.


10. The method according to claim 1, wherein the compound has thestructure shown below and the formula ZOC—CR₅R₆—CR₃R₄—CR₁R₂—COOH,wherein one of R₁ to R₆ is selected from the group consisting of SO₃H,OSO₃H, CH₂—SO₃H, CH₂—OSO₃H, and NHSO₃H, and the remaining are H or NH₂.


11. The method according to claim 1, wherein the compound has thestructure shown below and the formula ZOC—CR₇R₈—CR₅R₆—CR₃R₄—CR₁R₂—COOH,wherein one of R₁ to R8 is selected from the group consisting of SO3H,OSO3H, CH2—SO3H, CH2—OSO3H, and NHSO₃H, and the remaining are H or NH₂.


12. The method according to claim 9, wherein the compound is selectedfrom the group consisting of:
 1. L-Aspartic acid, N-Sulfonic acid, 2.L-Aspartic acid, 2β-sulfonic acid,
 3. L-Aspartic acid, 2β-sulfate, 4.L-aspartic acid, 3α-sulfonic acid,
 5. L-aspartic acid, 3α-sulfate, 6.L-aspartic acid, 3β-sulfonic acid,
 7. L-aspartic acid, 3f3-sulfate, 8.2α,3-dicarboxy, propane-1-sulfonic acid,
 9. 2α,3-dicarboxy,propane-1-sulfate,
 10. 1α,2-carboxy ethane sulfonic acid, 11.1α,2-carboxy ethane sulfate,
 12. D-aspartic acid, N-sulfonic acid, 13.2β,3-carboxy,propane-1-sulfonic acid, 14.2β,3-carboxy,propane-1-sulfate,
 15. 1β,2-carboxy ethane-1-sulfonic acid,16. 1β,2-carboxy ethane-1-sulfate,
 17. D-aspartic acid, 2α-sulfonicacid,
 18. D-aspartic acid, 2α-sulfonic acid,
 19. D-Aspartic acid,3α-sulfonic acid,
 20. D-Aspartic acid, 3α-sulfate,
 21. D-Aspartic acid,3β-sulfonic acid,
 22. D-aspartic acid, 3β-sulfate, 23.L-asparagine,N-sulfonic acid,
 24. 2α-carboxy, 3-carboxamido,propane-1-sulfonic acid,
 25. 2α-carboxy, 3-carboxamido,propane-1-sulfate,
 26. 1α-carboxy, 2-carboxamido, ethane sulfonic acid,27. 1α-carboxy, 2-carboxamido, ethane sulfate,
 28. L-asparagine,2β-sulfonic acid,
 29. L-asparagine, 2β-sulfate,
 30. L-asparagine,3α-sulfonic acid,
 31. L-asparagine, 3α-sulfate,
 32. L-asparagine,3β-sulfonic acid,
 33. L-asparagine, 3β-sulfate,
 34. D-asparagine,N-sulfonic acid,
 35. 2β-carboxy, 3-carboxamido, propane-1-sulfonic acid,36. 2β-carboxy, 3-carboxamido, propane-1-sulfate,
 37. 1β-carboxy,2-carboxamido, ethane sulfonic acid,
 38. 1β-carboxy, 2-carboxamido,ethane sulfate,
 39. D-asparagine, 2α-sulfonic acid,
 40. D-asparagine,2α-sulfate,
 41. D-asparagine, 3α-suifonic acid,
 42. D-asparagine,3α-sulfate,
 43. D-asparagine, 3β-sulfonic acid,
 44. D-asparagine,3β-sulfate.
 13. The method according to claim 10, wherein the compoundis selected from the group consisting of: (I) L-glutamic acid,N-sulfonic acid, (II) 2α,4-dicarboxy, butane-1-sulfonic acid, (III)2α,4-dicarboxy, butane-1-sulfate, (IV) 1α,3-dicarboxy, propane sulfonicacid, (V) 1α,3-dicarboxy, propane sulfate, (VI) 1β,3-dicarboxy, propanesulfate, (VII) 1β,3-dicarboxy, propane sulfonic acid, (VIII) L-glutamicacid, 2β-sulfonic acid, (IX) L-glutamic acid, 2β-sulfate, (X) L-glutamicacid, 3α-sulfonic acid, (XI) L-glutamic acid, 3α-sulfate, (XII)L-glutamic acid, 3β-sulfonic acid, (XIII) L-glutamic acid, 3β-sulfate,(XIV) L-glutamic acid, 4α-sulfonic acid, (XV) L-glutamic acid,4α-sulfate, (XVI) L-glutamic acid, 4β-sulfonic acid, (XVII) L-glutamicacid, 4β-sulfate, (XVIII) D-glutamic acid, N-sulfonic acid, (XIX)2β,4-dicarboxy, butane-1-sulfonic acid, (XX) 2β,4-dicarboxy,butane-1-sulfate, (XXI) D-glutamic acid, 2α-sulfonic acid, (XXII)D-glutamic acid, 2α-sulfate, (XXIII) D-glutamic acid, 3α-sulfonic acid,(XXIV) D-glutamic acid, 3α-sulfate, (XXV) D-glutamic acid, 3β-sulfonicacid, (XXVI0 D-glutamic acid, 3β-sulfate, (XXVII) D-glutamic acid,4α-sulfonic acid, (XXVIII) D-glutamic acid, 4α-sulfate, (XXIX)D-glutamic acid, 4β-sulfonic acid, (XXX) D-glutamic acid, 4β-sulfate,(XXXI) L-glutamine, N-sulfonic acid, (XXXII) L-glutamine, 2β-sulfonicacid, (XXXIII) L-glutamine, 2β-sulfate, (XXXIV) L-glutamine, 3α-sulfonicacid, (XXXV) L-glutamine, 3α-sulfate, (XXXVI) L-glutamine, 3β-sulfonicacid, (XXXVII) L-glutamine, 3β-sulfate, (XXXVIII) L-glutamine,4α-sulfonic acid, (XXXIX) L-glutamine, 4α-sulfate, (XL) L-glutamine,4β-sulfonic acid, (XLI) L-glutamine, 4β-sulfate, (XLII) 2α-carboxy,4-carboxamido, butane-1-sulfonic acid, (XLIII) 2α-carboxy,4-carboxamido, butane-1-sulfate, (XLIV) 1α-carboxy, 3-carboxamido,propane-1-sulfonic acid, (XLV) 1α-carboxy, 3-carboxamido,propane-1-sulfate, (XLVI) 1β-carboxy, 3-carboxamido, propane-1-sulfate,(XLVII) 1β-carboxy, 3-carboxamido, propane-1-sulfonic acid, (XLVIII)D-glutamine, N-sulfonic acid, (XLIX) 2β-carboxy, 4-carboxamido,butane-1-sulfonic acid, (L) 2β-carboxy, 4-carboxamido, butane-1-sulfate,(LI) D-glutamine, 2α-sulfonic acid, (LII) D-glutamine, 2α-sulfate,(LIII) D-glutamine, 3α-sulfonic acid, (LIV) D-glutamine, 3α-sulfate,(LV) D-glutamine, 3β-sulfonic acid, (LVI) D-glutamine, 3β-sulfate,(LVII) D-glutamine, 4α-sulfonic acid, (LVIII) D-glutamine, 4α-sulfate,(LIX) D-glutamine, 4β-sulfonic acid, (LX) D-glutamine, 4β-sulfate. 14.The method according to claim 11, wherein the compound is selected fromthe group consisting of: (I) L-homoglutamic acid, N-sulfonic acid, (II)Pentane-2α,5-dicarboxy-1-sulfonic acid, (III)Pentane-2α,5-dicarboxy-1-sulfate, (IV) Butane-1α,4-dicarboxy-1-sulfonicacid, (V) Butane-1α,4-dicarboxy-1-sulfate, (VI) L-homoglutamic acid,2β-sulfonic acid, (VII) L-homoglutamic acid, 2β-sulfate, (VIII)L-homoglutamic acid, 3α-sulfonic acid, (IX) L-homoglutamic acid,3α-sulfate, (X) L-homoglutamic acid, 3β-sulfonic acid, (XI)L-homoglutamic acid, 3β-sulfate, (XII) L-homoglutamic acid, 4α-sulfonicacid, (XIII) L-homoglutamic acid, 4α-sulfate, (XIV) L-homoglutamic acid,4β-sulfonic acid, (XV) L-homoglutamic acid, 4β-sulfate, (XVI)L-homoglutamic acid, 5α-sulfonic acid, (XVII) L-homoglutamic acid,5α-sulfate, (XVIII) L-homoglutamic acid, 5β-sulfonic acid, (XIX)L-homoglutamic acid, 5β-sulfate, (XX) D-homoglutamic acid, N-sulfonicacid, (XXI) Pentane-2β,5-dicarboxy-1-sulfonic acid, (XXII)Pentane-2β,5-dicarboxy-1-sulfate, (XXIII)Butane-1β,4-dicarboxy-1-sulfonic acid, (XXIV)Butane-1β,4-dicarboxy-1-sulfate, (XXV) D-homoglutamic acid, 2α-sulfonicacid, (XXVI) D-homoglutamic acid, 2α-sulfate, (XXVII) D-homoglutamicacid, 3α-sulfonic acid, (XXVIII) D-homoglutamic acid, 3α-sulfate, (XXIX)D-homoglutamic acid, 3β-sulfonic acid, (XXX) D-homoglutamic acid,3β-sulfate, (XXXI) D-homoglutamic acid, 4α-sulfonic acid, (XXXII)D-homoglutamic acid, 4α-sulfate, (XXXIII) D-homoglutamic acid,4β-sulfonic acid, (XXXIV) D-homoglutamic acid, 4β-sulfate, (XXXV)D-homoglutamic acid, 5α-sulfonic acid, (XXXVI) D-homoglutamic acid,5α-sulfate, (XXXVII) D-homoglutamic acid, 5β-sulfonic acid, (XXXVIII)D-homoglutamic acid, 5β-sulfate, (XXXIX) L-homoglutamine, N-sulfonicacid, (XL) Pentane-2α-carboxy, 5-carboxamido-1-sulfonic acid, (XYLI)Pentane-2α-carboxy, 5-carboxamido-1-sulfate, (XLII) Butane-1α-carboxy,4-carboxamido-1-sulfonic acid, (XLIII) Butane-1α-carboxy,4-carboxamido-1-sulfate, (XLIV) L-homoglutamine, 2β-sulfonic acid, (XLV)L-homoglutamine, 2β-sulfate, (XLVI) L-homoglutamine, 3α-sulfonic acid,(XLVII) L-homoglutamine, 3α-sulfate, (XLVIII) L-homoglutamine,3β-sulfonic acid, (XLIX) L-homoglutamine, 3β-sulfate, (L)L-homoglutamine, 4α-sulfonic acid, (LI) L-homoglutamine, 4α-sulfate,(LII) L-homoglutamine, 4β-sulfonic acid, (LIII) L-homoglutamine,4β-sulfate, (LIV) L-homoglutamine, 5α-sulfonic acid, (LV)L-homoglutamine, 5α-sulfate, (LVI) L-homoglutamine, 5β-sulfonic acid,(LVII) L-homoglutamine, 5β-sulfate, (LVIII) D-homoglutamine, N-sulfonicacid, (LIX) Pentane-2β-carboxy, 5-carboxamido-1-sulfonic acid, (LX)Pentane-2β-carboxy, 5-carboxamido-1-sulfate, (LXI) Butane-1β-carboxy,4-carboxamido-1-sulfonic acid, (LXII) Butane-1β-carboxy,4-carboxamido-1-sulfate, (LXIII) D-homoglutamine, 2α-sulfonic acid,(LXIV) D-homoglutamine, 2α-sulfate, (LXV) D-homoglutamine, 3α-sulfonicacid, (LXVI) D-homoglutamine, 3α-sulfate, (LXVII) D-homoglutamine,3β-sulfonic acid, (LXVIII) D-homoglutamine, 3β-sulfate, (LXIX)D-homoglutamine, 4α-sulfonic acid, (LXX) D-homoglutamine, 4α-sulfate,(LXXI) D-homoglutamine, 4β-sulfonic acid, (LXXII) D-homoglutamine,4β-sulfate, (LXXIII) D-homoglutamine, 5α-sulfonic acid, (LXXIV)D-homoglutamine, 5α-sulfate, (LXXV) D-homoglutamine, 5β-sulfonic acid,(LXXVI) D-homoglutamine, 5β-sulfate.